Methods of use and compositions for the diagnosis and treatment of infectious disease

ABSTRACT

Methods and compositions for treating disease caused by microorganisms, particularly tuberculosis. In particular, methods and compositions comprising substituted ethylene diamines for the treatment of infectious diseases are provided. In one embodiment, these methods and compositions are used for the treatment of mycobacterial infections, including, but not limited to, tuberculosis.

FIELD OF INVENTION

[0001] The present invention relates to methods and compositions for treating disease caused by microorganisms, particularly tuberculosis. The present invention also relates to methods and compositions having improved anti-mycobacterial activity, namely compositions comprising novel substituted ethylene diamine compounds.

BACKGROUND OF THE INVENTION

[0002] Mycobacterial infections often manifest as diseases such as tuberculosis. Human infections caused by mycobacteria have been widespread since ancient times, and tuberculosis remains a leading cause of death today. Although the incidence of the disease declined, in parallel with advancing standards of living, since the mid-nineteenth century, mycobacterial diseases still constitute a leading cause of morbidity and mortality in countries with limited medical resources. Additionally, mycobacterial diseases can cause overwhelming, disseminated disease in immunocompromised patients. In spite of the efforts of numerous health organizations worldwide, the eradication of mycobacterial diseases has never been achieved, nor is eradication imminent. Nearly one third of the world's population is infected with mycobacterium tuberculosis complex, commonly referred to as tuberculosis (TB), with approximately 8 million new cases, and two to three million deaths attributable to TB yearly. Tuberculosis (TB) is the cause of the largest number of human deaths attributable to a single etiologic agent (see Dye et al., J. Am. Med. Association, 282, 677-686, (1999); and 2000 WHO/OMS Press Release).

[0003] After decades of decline, TB is now on the rise. In the United States, up to 10 million individuals are believed to be infected. Almost 28,000 new cases were reported in 1990, constituting a 9.4 percent increase over 1989. A sixteen percent increase in TB cases was observed from 1985 to 1990. Overcrowded living conditions and shared air spaces are especially conducive to the spread of TB, contributing to the increase in instances that have been observed among prison inmates, and among the homeless in larger U.S. cities. Approximately half of all patients with “Acquired Immune Deficiency Syndrome” (AIDS) will acquire a mycobacterial infection, with TB being an especially devastating complication. AIDS patients are at higher risks of developing clinical TB, and anti-TB treatment seems to be less effective than in non-AIDS patients. Consequently, the infection often progresses to a fatal disseminated disease.

[0004] Mycobacteria other than M. tuberculosis are increasingly found in opportunistic infections that plague the AIDS patient. Organisms from the M. avium-intracellulare complex (MAC), especially serotypes four and eight, account for 68% of the mycobacterial isolates from AIDS patients. Enormous numbers of MAC are found (up to 10¹⁰ acid-fast bacilli per gram of tissue), and consequently, the prognosis for the infected AIDS patient is poor.

[0005] The World Health Organization (WHO) continues to encourage the battle against TB, recommending prevention initiatives such as the “Expanded Program on Immunization” (EPI), and therapeutic compliance initiatives such as “Directly Observed Treatment Short-Course” (DOTS). For the eradication of TB, diagnosis, treatment, and prevention are equally important. Rapid detection of active TB patients will lead to early treatment by which about 90% cure is expected. Therefore, early diagnosis is critical for the battle against TB. In addition, therapeutic compliance will ensure not only elimination of infection, but also reduction in the emergence of drug-resistance strains.

[0006] The emergence of drug-resistant M. tuberculosis is an extremely disturbing phenomenon. The rate of new TB cases proven resistant to at least one standard drug increased from 10 percent in the early 1980's to 23 percent in 1991. Compliance with therapeutic regimens, therefore, is also a crucial component in efforts to eliminate TB and prevent the emergence of drug resistant strains. Equally important is the development of new therapeutic agents that are effective as vaccines, and as treatments, for disease caused by drug resistant strains of mycobacteria.

[0007] Although over 37 species of mycobacteria have been identified, more than 95% of all human infections are caused by six species of mycobacteria: M. tuberculosis, M. avium intracellulare, M. kansasii, M. fortuitum, M. chelonae, and M. leprae. The most prevalent mycobacterial disease in humans is tuberculosis (TB) which is predominantly caused by mycobacterial species comprising M. tuberculosis, M. bovis, or M. africanum (Merck Manual 1992). Infection is typically initiated by the inhalation of infectious particles which are able to reach the terminal pathways in lungs. Following engulfment by alveolar macrophages, the bacilli are able to replicate freely, with eventual destruction of the phagocytic cells. A cascade effect ensues wherein destruction of the phagocytic cells causes additional macrophages and lymphocytes to migrate to the site of infection, where they too are ultimately eliminated. The disease is further disseminated during the initial stages by the infected macrophages which travel to local lymph nodes, as well as into the blood stream and other tissues such as the bone marrow, spleen, kidneys, bone and central nervous system. (See Murray et al. Medical Microbiology, The C. V. Mosby Company 219-230 (1990)).

[0008] There is still no clear understanding of the factors which contribute to the virulence of mycobacteria. Many investigators have implicated lipids of the cell wall and bacterial surface as contributors to colony morphology and virulence. Evidence suggests that C-mycosides, on the surface of certain mycobacterial cells, are important in facilitating survival of the organism within macrophages. Trehalose 6,6′ dimycolate, a cord factor, has been implicated for other mycobacteria.

[0009] The interrelationship of colony morphology and virulence is particularly pronounced in M. avium. M. avium bacilli occur in several distinct colony forms. Bacilli which grow as transparent, or rough, colonies on conventional laboratory media are multiplicable within macrophages in tissue culture, are virulent when injected into susceptible mice, and are resistant to antibiotics. Rough or transparent bacilli, which are maintained on laboratory culture media, often spontaneously assume an opaque R colony morphology, at which time they are not multiplicable in macrophages, are avirulent in mice, and are highly susceptible to antibiotics. The differences in colony morphology between the transparent, rough and opaque strains of M. avium are almost certainly due to the presence of a glycolipid coating on the surface of transparent and rough organisms which acts as a protective capsule. This capsule, or coating, is composed primarily of C-mycosides which apparently shield the virulent M. avium organisms from lysosomal enzymes and antibiotics. By contrast, the non-virulent opaque forms of M. avium have very little C-mycoside on their surface. Both the resistance to antibiotics and the resistance to killing by macrophages have been attributed to the glycolipid barrier on the surface of M. avium.

[0010] Diagnosis of mycobacterial infection is confirmed by the isolation and identification of the pathogen, although conventional diagnosis is based on sputum smears, chest X-ray examination (CXR), and clinical symptoms. Isolation of mycobacteria on a medium takes as long as four to eight weeks. Species identification takes a further two weeks. There are several other techniques for detecting mycobacteria such as the polymerase chain reaction (PCR), mycobacterium tuberculosis direct test, or amplified mycobacterium tuberculosis direct test (MTD), and detection assays that utilize radioactive labels.

[0011] One diagnostic test that is widely used for detecting infections caused by M. tuberculosis is the tuberculin skin test. Although numerous versions of the skin test are available, typically one of two preparations of tuberculin antigens are used: old tuberculin (OT), or purified protein derivative (PPD). The antigen preparation is either injected into the skin intradermally, or is topically applied and is then invasively transported into the skin with the use of a multiprong inoculator (Tine test). Several problems exist with the skin test diagnosis method. For example, the Tine test is not generally recommended because the amount of antigen injected into the intradermal layer cannot be accurately controlled. (See Murray et al. Medical Microbiology, The C. V. Mosby Company 219-230 (1990)).

[0012] Although the tuberculin skin tests are widely used, they typically require two to three days to generate results, and many times, the results are inaccurate since false positives are sometimes seen in subjects who have been exposed to mycobacteria, but are healthy. In addition, instances of mis-diagnosis are frequent since a positive result is observed not only in active TB patients, but also in persons vaccinated with Bacille Calmette-Guerin (BCG), and those who had been infected with mycobacteria, but have not developed the disease. It is hard therefore, to distinguish active TB patients from the others, such as household TB contacts, by the tuberculin skin test. Additionally, the tuberculin test often produces a cross-reaction in those individuals who were infected with mycobacteria other than M. tuberculosis (MOTT). Therefore, diagnosis using the skin tests currently available is frequently subject to error and inaccuracies.

[0013] The standard treatment for tuberculosis caused by drug-sensitive organisms is a six-month regimen consisting of four drugs given for two months, followed by two drugs given for four months. The two most important drugs, given throughout the six-month course of therapy, are isoniazid and rifampin. Although the regimen is relatively simple, its administration is quite complicated. Daily ingestion of eight or nine pills is often required during the first phase of therapy; a daunting and confusing prospect. Even severely ill patients are often symptom free within a few weeks, and nearly all appear to be cured within a few months. If the treatment is not continued to completion, however, the patient may experience a relapse, and the relapse rate for patients who do not continue treatment to completion is high. A variety of forms of patient-centered care are used to promote adherence with therapy. The most effective way of ensuring that patients are taking their medication is to use directly observed therapy, which involves having a member of the health care team observe the patient take each dose of each drug. Directly observed therapy can be provided in the clinic, the patient's residence, or any mutually agreed upon site. Nearly all patients who have tuberculosis caused by drug-sensitive organisms, and who complete therapy will be cured, and the risk of relapse is very low (“Ending Neglect: The Elimination of Tuberculosis in the United States” ed. L. Geiter Committee on the Elimination of Tuberculosis in the United States Division of Health Promotion and Disease Prevention, Institute of Medicine. Unpublished.)

[0014] What is needed are effective therapeutic regimens that include improved vaccination and treatment protocols. Currently available therapeutics are no longer consistently effective as a result of the problems with treatment compliance, and these compliance problems contribute to the development of drug resistant mycobacterial strains.

[0015] Ethambutol (EMB) is a widely used antibiotic for the treatment of TB, with over 300 million doses delivered for tuberculosis therapy in 1988.

[0016] Ethambutol, developed by Lederle Laboratories in the 1950s, has low toxicity and is a good pharmacokinetic. However, ethambutol has a relatively high Minimum Inhibition Concentration (MIC) of about 5 μg/ml, and can cause optic neuritis. Thus, there is an increasing need for new, and more effective, therapeutic compositions (See for example, U.S. Pat. No. 3,176,040, U.S. Pat. No. 4,262,122; U.S. Pat. No. 4,006,234; U.S. Pat. No. 3,931,157; U.S. Pat. No. 3,931,152; U.S. Re. No. 29,358; and Hausler et al., Bioorganic & Medicinal Chemistry Letters 11 (2001) 1679-1681). In the decoder years since the discovery of the beneficial effects of ethambutol, few pharmacological advances in TB treatment have been developed. Moreover, with the combined emergence of drug resistant strains, and the more prevalent spread of mycobacterial disease, it is becoming seriously apparent that new therapeutic compositions are crucial in the fight against tuberculosis.

[0017] Clearly effective therapeutic regimens that include improved vaccination and treatment protocols are needed. A therapeutic vaccine that would prevent the onset of tuberculosis, and therefore eliminate the need for therapy is desirable. Although currently available therapeutics such as ethambutol are effective, the emergence of drug resistant strains has necessitated new formulations and compositions that are more versatile than ethambutol. Currently available therapeutics are no longer consistently effective as a result of the problems with treatment compliance, lending to the development of drug resistant mycobacterial strains. What is needed are new anti-tubercular drugs that provide highly effective treatment, and shortens or simplifies tuberculosis chemotherapy.

SUMMARY OF THE INVENTION

[0018] The present invention comprises methods and compositions for the treatment of microorganisms, particularly methods and compositions comprising ethylene diamine compounds effective in the treatment of infectious organisms. The present invention also provides methods and compositions comprising substituted ethylene diamines having improved anti-mycobacterial activity, including substituted ethylene diamines having improved anti-tuberculosis activity.

[0019] The present invention contemplates substituted ethylene diamines, which can derive from a variety of amine compounds. In the present invention, the substituted ethylene diamines are based on the following structure.

[0020] The substituted ethylene diamine compounds described herein are synthesized and screened for activity as follows. A chemical library of substituted ethylene diamines is prepared on a solid polystyrene support using split and pool technologies. This technique allows for the synthesis of a diverse set of substituted ethylene diamines. These diamines are screened for anti-TB activity using in vitro, biological assays, including a High-Throughput Screening (HTS) assay, based on the recently completed genomic sequence of M tuberculosis, and a Minimum Inhibition Concentration (MIC) assay.

[0021] The methods and compositions described herein comprise substituted ethylene diamines that are effective against disease caused by microorganisms, but not limited to bacterial infection. One embodiment of the invention provides methods and compositions comprising substituted ethylene diamines that are effective against mycobacterial disease. Another embodiment of the invention provides methods and compositions comprising substituted ethylene diamines that have MIC of 50 μM or lower for mycobacterial disease. Another embodiment of the present invention comprises substituted ethylene diamines that have an MIC of 25 μM or lower for mycobacterial disease. Yet another embodiment of the present invention comprises substituted ethylene diamines that have an MIC of 12.5 μM or lower for mycobacterial disease. Another embodiment of the present invention comprises substituted ethylene diamines that have an MIC of 5 μM or lower for mycobacterial disease In another embodiment of the present invention, the methods and compositions comprise substituted ethylene diamines with HTS Luc activity of 10% or greater. In yet another embodiment of the present invention, the methods and compositions comprise substituted ethylene diamines, wherein one amine group is derived from a primary amine, and wherein the other amine group is derived from a primary or secondary amine. In another embodiment of the present invention, the methods and compositions comprise substituted ethylene diamines, wherein one amine is derived from cis-(−)myrtanylamine, cyclooctylamine, 2,2-diphenylethylamine, 3,3-diphenylpropylamine, (+)-bornylamine, 1-adamantanemethylamine, (+)-isopinocampheylamine; or isopinocampheylamine.

[0022] The present invention contemplates various salt complexes and other substituted derivatives of the substituted ethylene diamines. The present invention also contemplates enantiomers and other stereoisomers of the substituted ethylene diamines and their substituted derivatives. The present invention further contemplates treatment for animals, including, but not limited to, humans.

[0023] Accordingly, it is an object of the present invention to provide methods and compositions for the treatment and prevention of diseases caused by microorganisms.

[0024] Accordingly, it is an object of the present invention to provide methods and compositions for the treatment and prevention of infectious diseases.

[0025] Another object of the present invention is to provide methods and compositions for the treatment and prevention of mycobacterial disease, including but not limited to, tuberculosis.

[0026] Yet another object of the present invention is to provide methods and compositions for the treatment and prevention of infectious diseases using compositions comprising substituted ethylene diamines.

[0027] Another object of the present invention is to provide methods and compositions for the treatment and prevention of mycobacterial disease using compositions comprising substituted ethylene diamines.

[0028] Still another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines.

[0029] Another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein the diamine has an MIC of 50 μM, or less.

[0030] Another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein the diamine has an MIC of 25 μM, or less.

[0031] Another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein the diamine has an MIC of 12.5 μM, or less.

[0032] Yet another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein the diamine has an MIC of 5 μM, or less.

[0033] Yet another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein the diamine has HTS/Luc activity of 10% or greater.

[0034] Another object of the present invention is to provide methods and compositions for the treatment and prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein one amine group is derived from a primary amine, and the other amine group is derived from a primary or secondary amine.

[0035] Yet another object of the present invention is to provide methods and compositions for the treatment and/or prevention of tuberculosis using compositions comprising substituted ethylene diamines, wherein one amine is derived from cis-(−)myrtanylamine, cyclooctylamine, 2,2-diphenylethylamine, 3,3-diphenylpropylamine, (+)-bornylamine, 1-adamantanemethylamine, (+)-isopinocampheylamine; or (−)-isopinocampheylamine.

[0036] Yet another object of the present invention is to provide composition for the therapeutic formulation for the treatment and prevention of mycobacterial disease.

[0037] Another object of the present invention is to provide compositions for therapeutic formulations for the treatment and prevention of mycobacterial disease caused by mycobacterial species comprising M. tuberculosis complex, M. avium intracellulare, M. kansarii, M. fortuitum, M. chelonoe, M. leprae, M. africanum, M. microti, or M. bovis.

[0038] These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

[0039]FIG. 1 represents a flow schematic showing various solid support syntheses used to prepare substituted ethylene diamines.

[0040]FIG. 2 provides chemical structures of a variety of primary amines.

[0041]FIG. 3 provides chemical structures of a variety of acyclic secondary amines.

[0042]FIG. 4 provides chemical structures of a variety of cyclic secondary amines.

[0043]FIG. 5 represents a flow schematic for a representative reaction pool of ten substituted ethylene diamines.

[0044]FIG. 6 is a graph of Luminescence Count per Second (LCPS) versus concentration showing HTS Luc assay results for pooled substituted ethylene diamine compounds.

[0045]FIG. 7 is a graph of LCPS versus concentration showing HTS Luc assay results for individual substituted ethylene diamine compounds.

[0046]FIG. 8 is a graph of LCPS versus concentration showing HTS Luc assay results for individual substituted ethylene diamine compounds.

[0047]FIG. 9 is a bar graph providing a summary of MIC activities for discrete substituted ethylene diamines.

[0048]FIG. 10 is a bar graph providing a summary of Luciferase activity of discrete substituted ethylene diamines with at least 10% activity in reference to ethambutol at 3.1 μM.

[0049]FIG. 11 is a bar graph showing the frequency of occurrences of the selected amine monomers in the substituted ethylene diamine compounds that were active against TB. Amine monomers are represented by their numerical designations.

[0050]FIG. 12 represents a flow schematic showing a synthesis of N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine (compound 109).

[0051]FIG. 13 is a flow schematic showing a synthesis of N-(Cyclooctyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine as hydrochloride (compound 59).

[0052]FIG. 14 is a mass spec profile for one representative sample well containing pooled substituted ethylene diamine compounds.

[0053]FIG. 15 is a mass spec profile for compound 109, N-Geranyl-N′-(2-adamanthyl) ethane-1,2-diamine.

[0054]FIG. 16 is a proton NMR profile for compound 109, N-Geranyl-N′-(2-adamanthyl) ethane-1,2-diamine.

[0055]FIG. 17 is a bar graph of data from a Colony Forming Units/Lung (CFU/Lung) study showing CFU/Lung growth over time in days for various compounds.

[0056]FIG. 18 is a bar graph of data from a CFU/Lung study showing CFU/Lung growth over time in days for various compounds.

[0057]FIG. 19 is a bar graph of data from a CFU/Lung study showing CFU/Lung growth over time in days for various compounds.

[0058]FIG. 20 is a bar graph of data from a lesion study showing visible lesions over time after treatment with various compounds.

DETAILED DESCRIPTION

[0059] The present invention may be understood more readily by reference to the following detailed description of the specific embodiments included herein. However, although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention.

[0060] Mycobacterial infections, such as those causing tuberculosis, once thought to be declining in occurrence, have rebounded, and again constitute a serious health threat. Tuberculosis (TB) is the cause of the largest number of human deaths attributed to a single etiologic agent with two to three million people infected with tuberculosis dying each year. Areas where humans are crowded together, or living in substandard housing, are increasingly found to have persons affected with mycobacteria. Individuals who are immunocompromised are at great risk of being infected with mycobacteria and dying from such infection. In addition, the emergence of drug-resistant strains of mycobacteria has led to treatment problems of such infected persons.

[0061] Many people who are infected with mycobacteria are poor, or live in areas with inadequate healthcare facilities. As a result of various obstacles (economical, education levels, etc.), many of these individuals are unable to comply with the prescribed therapeutic regimens. Ultimately, persistent non-compliance by these and other individuals results in the prevalence of disease. This noncompliance is frequently compounded by the emergence of drug-resistant strains of mycobacteria. Effective compositions and vaccines that target various strains of mycobacteria are necessary to bring the increasing number of tuberculosis cases under control.

[0062] Chemotherapy is a standard treatment for tuberculosis. Some current chemotherapy treatments require the use of three or four drugs, in combination, administered daily for two months, or administered biweekly for four to twelve months. Table 1 lists several treatment schedules for standard tuberculosis drug regimens. TABLE 1 Treatment Schedules for Standard TB Drug Regimens. INDUCTION STANDARD PHASE CONTINUATION DRUG Dosing PHASE REGIMEN Schedule DURATION DRUG Dosing Schedule DURATION Isoniazid Daily, DOT 8 weeks Isoniazid 2/week, DOT 16 weeks Rifampicin Daily, DOT 8 weeks Rifampien 2/week, DOT 16 weeks Pyrazinamide Daily, DOT 8 weeks Ethambutol or Daily, DOT 8 weeks Streptomycin

[0063] Decades of misuse of existing antibiotics and poor compliance with prolong and complex therapeutic regimens has led to mutations of the mycobacterium tuberculosis and has created an epidemic of drug resistance that threatens tuberculosis control world wide. The vast majority of currently prescribed drugs, including the front line drugs, such as isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin were developed from the 1950s to the 1970s. Thus, this earlier development of tuberculosis chemotherapy did not have at its disposal the implications of the genome sequence of Mycobacterium tuberculosis, the revolution in pharmaceutical drug discovery of the last decades, and the use of national drug testing and combinational chemistry.

[0064] Consequently, the treatments of drug-resistant M. tuberculosis strains, and latent tuberculosis infections, require new anti-tuberculosis drugs that provide highly effective treatments, and shortened and simplified tuberculosis chemotherapies. Moreover, it is desirable that these drugs be prepared by a low-cost synthesis, since the demographics of the disease dictate that cost is a significant factor.

[0065] The present invention provides methods and compositions comprising a class of substituted ethylene diamine compounds effective in treatment and prevention of disease caused by microorganisms including, but not limited to, bacteria. In particular, the methods and compositions of the present invention are effective in inhibiting the growth of the microorganism, M. tuberculosis. The methods and compositions of the present invention are intended for the treatment of mycobacteria infections in human, as well as other animals. For example, the present invention may be particularly useful for the treatment of cows infected by M. bovis.

[0066] As used herein, the term “tuberculosis” comprises disease states usually associated with infections caused by mycobacteria species comprising M. tuberculosis complex. The term “tuberculosis” is also associated with mycobacterial infections caused by mycobacteria other than M. tuberculosis (MOTT). Other mycobacterial species include M. avium-intracellulare, M. kansarii, M. fortuitum, M. chelonae, M. leprae, M. africanum, or M. microti.

[0067] The anti-infective methods and compositions of the present invention contain one or more substituted ethylene diamine compounds. In particular, these compounds encompass a wide range of substituted ethylene diamine compounds having the following general formula:

[0068] where “R₁NH” is typically derived from a primary amine, and “R₂R₃N” is typically derived from a primary or secondary amine. The ethylene diamines of the present invention are prepared by a modular approach using primary and secondary amines as building blocks, and coupling the amine moieties with an ethylene linker building block. Representative primary amines, acyclic secondary amines, and cyclic secondary amines are shown in FIGS. 2, 3, and 4, respectively.

[0069] Generally, chemical moieties R₁, R₂, and R₃ of the ethylene diamine compounds of the present invention are independently selected from H, alkyl; aryl; alkenyl; alkynyl; aralkyl; aralkenyl; aralkynyl; cycloalkyl; cycloalkenyl; heteroalkyl; heteroaryl; halide; alkoxy; aryloxy; alkylthio; arylthio; silyl; siloxy; a disulfide group; a urea group; amino; and the like, including straight or branched chain derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, heterocyclic derivatives thereof, functionalized derivatives thereof, salts thereof, such salts including, but not limited to hydrochlorides and acetates, isomers thereof, or combinations thereof. For example, nitrogen-containing heterocyclic moieties include, but are not limited to, groups such as pyridinyl (derived from pyridine, and bonded through a ring carbon), piperidinyl (derived from piperidine and bonded through the ring nitrogen atom or a ring carbon), and pyrrolidinyl (derived from pyrrolidine and bonded through the ring nitrogen atom or a ring carbon). Examples of substituted, or functionalized, derivatives of R₁, R₂, and R₃ include, but are not limited to, moieties containing substituents such as acyl, formyl, hydroxy, acyl halide, amide, amino, azido, acid, alkoxy, aryloxy, halide, carbonyl, ether, ester, thioether, thioester, nitrile, alkylthio, arythio, sulfonic acid and salts thereof, thiol, alkenyl, alkynyl, nitro, imine, imide, alkyl, aryl, combinations thereof, and the like. Moreover, in the case of alkylated derivatives of the recited moieties, the alkyl substituent may be pendant to the recited chemical moiety, or used for bonding to the amine nitrogen through the alkyl substituent.

[0070] Examples of chemical moieties R₁, R₂, and R₃ of the present invention include, but are not limited to: H; methyl; ethyl; propyl; butyl; pentyl; hexyl; heptyl; octyl; ethenyl; propenyl; butenyl; ethynyl; propynyl; butynyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclooctyl cyclobutenyl; cyclopentenyl; cyclohexenyl; phenyl; tolyl; xylyl; benzyl; naphthyl; pyridinyl; furanyl; tetrahydro-1-napthyl; piperidinyl; indolyl; indolinyl; pyrrolidinyl; 2-(methoxymethyl) pyrrolidinyl; piperazinyl; quinolinyl; quinolyl; alkylated-1,3-dioxolane; triazinyl; morpholinyl; phenyl pyrazolyl; indanyl; indonyl; pyrazolyl; thiadiazolyl; rhodaninyl; thiolactonyl; dibenzofuranyl; benzothiazolyl; homopiperidinyl; thiazolyl; quinonuclidinyl; isoxazolidinonyl; any isomers, derivatives, or substituted analogs thereof; or any substituted or unsubstituted chemical species such as alcohol, ether, thiol, thioether, tertiary amine, secondary amine, primary amine, ester, thioester, carboxylic acid, diol, diester, acrylic acid, acrylic ester, methionine ethyl ester, benzyl-1-cysteine ethyl ester, imine, aldehyde, ketone, amide, or diene. Further examples of chemical moieties R₁, R₂, and R₃ of the present invention include, but are not limited to, the following species or substituted or alkylated derivatives of the following species, covalently bonded to the amine nitrogen: furan; tetrahydrofuran; indole; piperazine; pyrrolidine; pyrrolidinone; pyridine; quinoline; anthracene; tetrahydroquinoline; naphthalene; pyrazole; imidazole; thiophene; pyrrolidine; morpholine; and the like. One feature of the recited species or substituted or alkylated derivatives of these species, is that they may be covalently bonded to the amine nitrogen in any fashion, including through the pendant substituent or alkyl group, through the heteroatom as appropriate, or through a ring atom as appropriate, as understood by one of ordinary skill in the art.

[0071] The chemical moieties R₁, R₂, and R₃ of the present invention also include, but are not limited to, cyclic alkanes and cyclic alkenes, and include bridged and non-bridged rings. Examples of bridged rings include, but are not limited to, the following groups: isopinocamphenyl; bornyl; norbornyl; adamantanetetyl; cis-(−)myrtanyl; adamantyl; noradamantyl; 6-azabicyclo[3.2.1]octane; exo-norbornane; and the like.

[0072] In one embodiment of the present invention, NR₂R₃ is derived from a cyclic secondary amine. Examples of a cyclic chemical moiety, NR₂R₃, of the present invention include, but are not limited to, 4-benzyl-piperidine; 3-piperidinemethanol; piperidine; tryptamine; moropholine; 4-piperidinopiperidine; ethyl 1-piperazine carboxylate; 1-(2-amino-ethyl)-piperazine; decahydroquinoline; 1,2,3,4-tetrahydro-pyridoindole (reaction at either amine); 3-amino-5-phenyl pyrazole; 3-aminopyrazole; 1-(2-fluorophenyl) piperazine; 1-proline methyl ester; histidinol; 1-piperonyl-piperazine; hexamethyleimine; 4-hydroxypiperidine; 2-piperidinemethanol; 1,3,3-trimethyl-6-azabicyclo[3.2.1] octane; 3-pyrrolidinol; 1-methylpiperazine; (S)-(+)-(2-pyrolidinylmethyl) pyrrolidine; 1-methylhomopiperazine; 2-ethyl-piperidine; 1,2,3,4-tetrahydroisoquinoline; 1-(4-fluorophenyl) piperazine; d,l-tryptophan methyl ester; tert-butyl (15, 45)-(−)-2,5-diazabiclyclo[2.2.1] heptane-2-carboxylate; isonipecotamide; heptamethyleneimine; alpha-methyltryptamine; 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 3-aminopyrrolidine; 3,5-dimethylpiperidine; 2,6-dimethylmorpholine; 1,4-dioxo-8-azaspiro[4.5]decane; 1-methol-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; 1,3,4,6,7,8-hexahydro-2H-pyrido (1,2-A) pyrimidine; 1,2,3,4-tetrahydroquinoline; 1-(2-methoxyphenyl) piperazine; 1-(2-(2-hydroxyethoxy)ethyl) piperazine; (S)-(+)-2-(aminomethyl) pyrroli-dine; (3S(3a,4Ab),8Ab)-N-t-butyl-D-ecahydro-3-isoquino-linecarboxamide; (R)-cycloserine; homopiperazine; 2,6-dimethylpiperazine (reaction at either amine); iminodibenzyl; 5-methoxytryptamine; 4,4′-bipiperidine; 1-(2-hydroxyethyl) piperazine; 4-methylpiperidine; 1-histidine methyl ester; or methyl pipecoliate.

[0073] The R₁HN substituent is derived from a primary amine. The R₂R₃N substituent is typically derived from a primary or secondary amine, but may also arise from an amino acid, or an amino acid precursor. The amino acid can transform into an amino alcohol. When an amino acid is employed as the source of the R₂R₃N moiety, the precursor compound may be selected from, among others, the following compounds and their derivatives: d,l-tryptophan methyl ester; 1-methionine ethyl ester; 1-lysine methyl ester (via reaction at either primary amine); (S)-benzyl-1-cysteine ethyl ester; 1-arginine methyl ester (via reaction at either primary amine); 1-glutamic acid ethyl ester; 1-histidine methyl ester; or (3S(3a,4Ab),8Ab)-N-t-butyl-D-ecahydro-3-iso-quino linecarboxamide.

[0074] The R₄ moiety of the substituted ethylene diamine compounds of the present invention is typically selected from H, alkyl or aryl, but R₄ can also constitute alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, and the like. Examples of the R₄ chemical moiety include, but are not limited to: H; methyl; ethyl; propyl; butyl; pentyl; hexyl; heptyl; octyl; ethenyl; propenyl; butenyl; ethynyl; propynyl; butynyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclobutenyl; cyclopentenyl; cyclohexenyl; phenyl; tolyl; xylyl; benzyl; naphthyl; straight or branched chain derivatives thereof; cyclic derivatives thereof; substituted, functionalized, and heteroatom derivatives thereof; and heterocyclic derivatives thereof, and the like. Typically, R₄ is selected from H, methyl, ethyl, butyl or phenyl. However, when R₄ is “H” the ethylene diamine does not contain ethambutol.

[0075] A majority of the ethylene diamine compounds described hrein are preferably prepared using a solid support synthesis, as set forth in one of the representative reaction schemes shown in FIG. 1. However, when R₄ is H, the reaction does not proceed well when sterically hindered amines are used for R₁NH₂, or when diamines, such as amino alkylenemorpholine, or aminoalkylene-piperidines, are used for R₁NH₂. When R₄ is methyl, or phenyl, sterically hindered amines used for R₃R₂NH do not work well due to steric hindrance at the reaction site. In this case, a competing hydrolysis reaction producing the corresponding amino alcohols, and incomplete reduction of the amidoethyleneamines, interfere with the reaction scheme. As a result, the desired diamine products form in low yields.

[0076] The preparation of the ethylene diamines is preferably accomplished in six steps, using a rink-acid resin. The first step of the synthesis is converting the rink-acid resin to rink-chloride by treatment with triphenylphosphine and hexachloroethane in tetrahydrofuran (THF). This step is followed by addition of the primary amine in the presence of Hunig's base (EtN(i-Pr)₂) in dichloroethane. The third step is the acylation of the resin-attached amine using either one of the two acylation routes shown in FIG. 1. The acylation step is preferably accomplished using either chloroacetyl chloride, α-bromo-α-methyl acetylbromide, α-bromo-α-ethylacetyl bromide, α-bromo-α-butyl acetylbromide, or α-chloro-α-phenyl-acetylchloride, each in the presence of pyridine in THF. Other acylation reagents known to those skilled in the art may also be used, however, the α-bromoacetyl halides result in low product yields, which may be attributed to HBr elimination. The acylation may also be accomplished via a peptide coupling mechanism using α-bromo-α-methylacetic acid, or α-chloro-α-methylacetic acid, in the presence of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop) and N,N-diisopropylethyl amine (EtN(i-Pr)₂) in dichloromethane (DCM) and dimethylformamide (DMF). Again, other acylation reagents known to those skilled in the art may also be used. The acylation step is preferably performed twice to achieve better acylated product yields.

[0077] Introduction of the second nitrogen moiety is preferably achieved in the presence of Hunig's base in dimethylformamide (DMF). Reduction of the intermediate amine-amide is carried out using Red-Al (3.4M solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene). The final product is cleaved from the resin support using a 10% solution (by volume) of trifluoroacetic acid (TFA) in dichloromethane (DCM). The solvent is evaporated, and the TFA salts of the final diamine products are analyzed by mass spec, and screened against M. tuberculosis for effectiveness. Some of the substituted ethylene diamines, prepared using the above-described solid-support synthesis, are also prepared using a solution phase synthesis described below.

[0078] Formation of the Substituted Ethylene Diamine Library

[0079] The solid support syntheses, shown in FIG. 1, are preferably used to prepare a substituted ethylene diamine library. Solid phase synthesis offers at least three principal advantages: (i) a reduced need for chromatographic procedures, (ii) the use of excess reagents to drive a reaction forward in high yields, and (iii) the use of split and pool technologies for the synthesis of a large number of compounds. Solid support syntheses of 1,2-diamine libraries have previously been accomplished by the reduction of short peptides (Cuervo et al., Peptides 1994: Proceedings of the European Peptide Symposium; Maia HSL Ed., Esom: Leiden, 1995, 465-466). However, as described herein, an ethylene diamine library is created using amines, rather than simple amino acids, to allow for greater diversity in the building-block monomers. The first three steps of each support synthesis: the activation of the Rink-acid resin, the addition of the first amine, and the acylation step are carried out in 10 ml tubes on a QUEST® 210 Synthesizer manufactured by ARGONAUT TECHNOLOGIES®, Inc., Foster City, Calif. The synthesizer handles up to twenty simultaneous reactions in 5 ml or 10 ml reaction vessels to allow for rapid synthesis of target compounds. The synthesizer provides programmable temperature control and agitation, and the automated delivery of solvents into the reaction vessels. The addition of the second amine, the reduction with Red-Al, and the cleavage from the solid support are carried out in 2 ml wells in a 96-well, chemically resistant plate.

[0080] Prior to the solid support synthesis, each amine, within numbers 1 to 288, as shown in FIGS. 2, 3, and 4, is dissolved in DMF as a one molar solution, and organized in three, 96-well plates (one amine per well), to yield three master plates of these amines. An individual haloacetyl amide from each primary amine and a particular R₄ group, is formed in the first three steps of the support synthesis. Individual haloacetyl amides are then pooled into groups of ten or thirty. A suspension of the pooled resins in a 2:1 mixture of DCM/THF is evenly distributed into one, two or three reaction plates to assure 15-20 mg of the suspension per well. The number of reaction plates used is based on the amount of suspension available. Each well of pooled resins is reacted with a corresponding amine from the master plates. FIG. 5 provides a flow schematic for a representative pool. Each reaction occurs in a separate well, in the presence of Hunig's base in DMF at 70-75° C. for 16-20 hours. Each resulting amine-amide is reduced using 65+w % Red-Al at room temperature. The reduction is followed by cleavage with 10% vol. TFA in DCM. The solvents in each reaction well are evaporated, and the TFA salts of the diamines analyzed (mass spec), and screened against M. tuberculosis. One plate of pooled diamines are screened against M. smegmatis. Two randomly selected rows in each plate; i.e., 24 samples per 96-well plate, or 25% of the library, are examined by mass spectroscopy. Specific protocols and detailed methods are provided below in the Examples.

[0081] Screening Against M. tuberculosis

[0082] An entire library of synthesized substituted ethylene diamines (targeted number of compounds about 100,000), prepared as described above, was screened, in vitro, against M. tuberculosis in ethambutol (EMB) sensitive Luc-assay. The MIC (Minimum Inhibition Concentration) was also determined. The MIC is the concentration of a growth inhibitor, here the substituted ethylene diamine, in which there is no multiplication of the microorganism under examination. Screening was done using a High-Throughout Screening (HTS) Luc assay with recombinant mycobacteria containing a promoter fusion of a luciferase to the EB-inducible gene (Luc assay). The Luc-assay and MIC assay are described in detail below. These assays are well known to those skilled in the art. Based on this initial screening, 300+ compound mixtures showed anti-TB activity. FIG. 6 represents typical assay data in a luciferase reporter strain containing an Rv0341 EMB-inducible promoter. FIG. 6 represents percent maximum Luminescense Count per Second (% Max. LCPS) for pooled compound mixtures in one row (row D) in one of the 96-well plates.

[0083] Deconvolution of the Reactive Wells

[0084] The M. tuberculosis screening revealed approximately 300 active compounds mixtures that were selected for deconvolution. In particular, wells possessing activity of approximately <12.5 μM in the HTS Luc assay, and/or an MIC of approximately <12.5 μM, were selected for a total of 336 wells.

[0085] Deconvolutions were performed by discrete re-synthesis of each substituted ethylene diamine compound in each active compound pool. The pooled compounds in each active well were individually synthesized, and screened. Syntheses of the targeted diamine compounds in each active pool were done in the 96-well plates using stored archived α-haloacetyl amides (resin attached haloacetyl amides), according to the previously described reaction steps (the addition of the second amine, the reduction with Red-Al, and the cleavage from the solid support). The archived resins were stored as individual compounds at 4° C. The 96-well plates were used for the remaining synthesis steps as previously described.

[0086] The same screening tests, MIC and HTS Luc assay, were performed on each deconvoluted compound. Representative Luminescence data for deconvoluted compounds are shown in FIGS. 7 and 8. FIGS. 7 and 8 represent the Luminescence Count per Second (LCPS) for individual compounds.

[0087] Summary of Screening Results

[0088] Overall, the deconvolution screening results (revealed about 2,000 ethylene diamine compounds with inhibitory activity against M. tuberculosis. More than 150 of these compounds exhibited MICs equal to or lower than approximately 12.5 μM. FIG. 9 summarizes the MIC data for all synthesized discrete compounds with an MIC of 50 μM or less. FIG. 10 summarizes Luc assay data for all compounds that exhibit at least 10% activity at each concentration (the results are not cumulative). The MIC and Luc activities were obtained for non-purified samples, with chemical yields of approximately 20%, based on an assumed 80% yield at each reaction step. In the Luc assay, 32 compounds exhibited activity at 1.56 μM, and in the MIC assay, at least 11 compounds had an MIC of 3.13 μM.

[0089] The total frequency of the top thirteen amines that contributed to the activity of the substituted ethylene diamines are shown in FIG. 11, with each amine represented by its numerical designation. These amines include the following:

[0090] #11 2,3-Dimethylcylochexy amines

[0091] #18 3,3-Diphenylpropylamine

[0092] #44 1-Adamantanemethylamine

[0093] #47 2,2-Diphenylethylamine

[0094] #63 (S)-2-Amino-1-butanol

[0095] #74.1 (−)-cis-Myrtanyl amine

[0096] #77.1 Cyclooctylamine

[0097] #78.1 2-Adamantamine

[0098] #105a (1R,2R,3R,5S)-(−)-Isopinocampheylamine

[0099] #231 2-Methoxyphenethylamine

[0100] #255 (S)-Cylcohexylethylamine

[0101] #266 Undecylamine

[0102] #272 Geranylamine

[0103] Other amines that contributed to the activity of the substituted ethylene diamines are shown in Table 2. The compounds in Table 2 are sorted by their MIC results. Some compounds, synthesized in larger quantities (2-60 mg) on the Quest® Synthesizer, and purified by HPLC using semi-preparative C18-column, are shown in Table 3. Generally, the final purity of each compound in Table 3 was at least 90%. TABLE 2 Synthetic Substituted Diethylene Diamines Sorted by Minimum Inhibition Concentration MIC % N1 N2 R4 (uM) Induction 3,3-Diphenylpropylamine exo-Aminonorbornane Hydrogen 3.13 53.70 2,2-Diphenylamine (+)-Isopinocampheylamine Hydrogen 3.13 93.94 2,2-Diphenylamine cis-(−)-Myrtanylamine Hydrogen 3.13 64.49 2,2-Diphenylamine Cyclooctylamine Hydrogen 3.13 63.44 2,2-Diphenylamine 3,4-Dihydroxynorephedrine Hydrogen 3.13 42.80 5-Aminoquinoline Cyclohexylamine Hydrogen 3.13 18.33 5-Aminoquinoline tert-Octylamine Hydrogen 3.13 20.85 5-Aminoquinoline 4-Methylcyclohexylamine Hydrogen 3.13 26.33 cis-(−)-Myrtanylamine (+)-Bornylamine Hydrogen 3.13 100.00 cis-(−)-Myrtanylamine 1-Adamantanemethylamine Hydrogen 3.13 85.20 cis-(−)-Myrtanylamine (−)-Isopinocampheylamine Hydrogen 3.13 60.94 1-Adamantanemethylamine tert-Octylamine Hydrogen 4.7 9.81 3,4-Dimethoxyphenethylamine 1-Adamantanemethylamine Hydrogen 6.25 11.45 3,4-Dimethoxyphenethylamine Hexetidine (mixture of isomers) Hydrogen 6.25 0 3,4-Dimethoxyphenethylamine Dehydroabietylamine Hydrogen 6.25 0 3,3-Diphenylpropylamine 1-Adamantanemethylamine Hydrogen 6.25 9.53 3,3-Diphenylpropylamine 2-Methylcyclohexylamine Hydrogen 6.25 50.08 (mix of cis and trans) 3,3-Diphenylpropylamine 1,3-Dimethylbutylamine Hydrogen 6.25 39.40 3,3-Diphenylpropylamine 1-(1-Adamantyl)ethylamine, Hydrogen 6.25 45.14 HCl 3,3-Diphenylpropylamine (S)-(−)-Cyclohexylethylamine Hydrogen 6.25 43.49 3,3-Diphenylpropylamine (R)-(−)-Cyclohexylethylamine Hydrogen 6.25 34.54 3,3-Diphenylpropylamine 1-Adamantanemethylamine Methyl 6.25 16.14 Propylamine Hexetidine (mixture of isomers) Hydrogen 6.25 0 Phenethylamine Hexetidine (mixture of isomers) Hydrogen 6.25 0 b-Methylphenethylamine Hexetidine (mixture of isomers) Hydrogen 6.25 0 b-Methylphenethylamine Undecylamine Hydrogen 6.25 0 2,2-Diphenylamine (+)-Bornylamine Hydrogen 6.25 87.86 2,2-Diphenylamine (−)-Isopinocampheylamine Hydrogen 6.25 77.80 2,2-Diphenylamine alpha-Methyltryptamine Hydrogen 6.25 55.07 2,2-Diphenylamine alpha-Methyltryptamine Hydrogen 6.25 23.08 2,2-Diphenylamine 4-Phenylbutylamine Hydrogen 6.25 2,2-Diphenylamine 2,5-Dimethoxyphenethylamine Hydrogen 6.25 2,2-Diphenylamine 2,4-Dichlorophenethylamine Hydrogen 6.25 2,2-Diphenylamine 2-(2-Aminomethyl) Hydrogen 6.25 phenylthio)benzyl alcohol 2,2-Diphenylamine 1-(1-Naphthyl)ethylamine Hydrogen 6.25 7.20 Veratryl amine 2,5-Dimethoxyphenethylamine Hydrogen 6.25 Veratryl amine 2-(2-Aminomethyl) Hydrogen 6.25 phenylthio)benzyl alcohol 5-Aminoquinoline 2-Aminoheptane Hydrogen 6.25 26.22 5-Aminoquinoline 1-Adamantanamine Hydrogen 6.25 18.91 1-Aminomethyl-1- Hexetidine (mixture of isomers) Hydrogen 6.25 cyclohexanol, HCl cis-(−)-Myrtanylamine 2,3-Dimethylcyclohexylamine Hydrogen 6.25 100.00 cis-(−)-Myrtanylamine 3,3-Diphenylpropylamine Hydrogen 6.25 87.78 cis-(−)-Myrtanylamine (+)-Isopinocampheylamine Hydrogen 6.25 93.10 cis-(−)-Myrtanylamine 2,2-Diphenylamine Hydrogen 6.25 81.84 cis-(−)-Myrtanylamine cis-(−)-Myrtanylamine Hydrogen 6.25 68.24 cis-(−)-Myrtanylamine 1,3,3-Trimethyl-6- Hydrogen 6.25 68.18 azabicyclo[3.2.1]octane cis-(−)-Myrtanylamine 1-Adamantanemethylamine Methyl 6.25 24.22 cis-(−)-Myrtanylamine cis-(−)-Myrtanylamine Methyl 6.25 44.14 Cyclooctylamine 3,3-Diphenylpropylamine Hydrogen 6.25 100.00 Cyclooctylamine (−)-Isopinocampheylamine Hydrogen 6.25 59.13 sec-Butylamine Hexetidine (mixture of isomers) Hydrogen 6.25 3-Methylbenzylamine Hexetidine (mixture of isomers) Hydrogen 6.25 3-Methylbenzylamine Undecylamine Hydrogen 6.25 2-Methoxyethylamine Hexetidine (mixture of isomers) Hydrogen 6.25 Geranylamine 2-Adamantanamine, HCl Hydrogen 6.25 25.66 1-Adamantanemethylamine 4-Benzylpiperidine Hydrogen 9.4 0 1-Adamantanemethylamine 2,3-Dimethylcyclohexylamine Hydrogen 9.4 0 1-Adamantanemethylamine 3,3-Diphenylpropylamine Hydrogen 9.4 40.06 1-Adamantanemethylamine 1-Adamantanemethylamine Hydrogen 9.4 15.25 1-Adamantanemethylamine 2,2-Diphenylamine Hydrogen 9.4 0 1-Adamantanemethylamine 1,3,3-Trimethyl-6- Hydrogen 9.4 0 azabicyclo[3.2.1]octane 1-Adamantanemethylamine 138 Hydrogen 9.4 0 3-Phenyl-1-propylamine 138 Hydrogen 9.4 2,2-Diphenylamine 1-Adamantanemethylamine Hydrogen 9.4 65.89 2,2-Diphenylamine 138 Hydrogen 9.4 Furfurylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 3,4,5-Trimethoxybenzylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 1-Methyl-3-phenylpropylamine Dehydroabietylamine Hydrogen 12.5 0 Cyclobutylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 2-Fluorobenzylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 2-Fluorobenzylamine Dehydroabietylamine Hydrogen 12.5 0 3,4-Dimethoxyphenethylamine Undecylamine Hydrogen 12.5 0 3,3-Diphenylpropylamine exo-Aminonorbornane Hydrogen 12.5 14.38 3,3-Diphenylpropylamine Decahydroquinoline Hydrogen 12.5 22.52 3,3-Diphenylpropylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 3,3-Diphenylpropylamine 4-Phenylbutylamine Hydrogen 12.5 0 3,3-Diphenylpropylamine 2-Methoxyphenethylamine Hydrogen 12.5 6.82 3,3-Diphenylpropylamine 2,4-Dichlorophenethylamine Hydrogen 12.5 0 3,3-Diphenylpropylamine 1-Aminoindan Hydrogen 12.5 18.05 3,3-Diphenylpropylamine Undecylamine Hydrogen 12.5 0 3,3-Diphenylpropylamine Dehydroabietylamine Hydrogen 12.5 0 3,3-Diphenylpropylamine 2-(1-Cyclohexenyl)ethylamine Methyl 12.5 9.5 3,3-Diphenylpropylamine cis-(−)-Myrtanylamine Methyl 12.5 18.41 3,3-Diphenylpropylamine Cyclooctylamine Methyl 12.5 20.84 Propylamine Dehydroabietylamine Hydrogen 12.5 0 Phenethylamine Dehydroabietylamine Hydrogen 12.5 0 Cyclohexylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 3-Amino-1-propanol Hexetidine (mixture of isomers) Hydrogen 12.5 0 b-Methylphenethylamine Dehydroabietylamine Hydrogen 12.5 0 4-Methoxyphenethylamine 2-Fluorophenethylamine Hydrogen 12.5 0 4-Methoxyphenethylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 12.5 0 4-Methoxyphenethylamine 2,4-Dimethoxybenzylamine Hydrogen 12.5 0 4-Methoxyphenethylamine 4-Fluorophenethylamine Hydrogen 12.5 16.78 4-Methoxyphenethylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 Tetrahydrofurfurylamine Hexetidine (mixture of isomers) Hydrogen 12.5 0 Amylamine 4-Fluorophenethylamine Hydrogen 12.5 0 3-Phenyl-1-propylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 12.5 3-Phenyl-1-propylamine 4-Fluorophenethylamine Hydrogen 12.5 12.94 2,2-Diphenylamine tert-Amylamine Hydrogen 12.5 9.05 2,2-Diphenylamine Undecylamine Hydrogen 12.5 2,2-Diphenylamine Dehydroabietylamine Hydrogen 12.5 2,2-Diphenylamine cis-(−)-Myrtanylamine Methyl 12.5 45.18 1-(3-Aminopropyl)-2- 2,5-Dimethoxyphenethylamine Hydrogen 12.5 pyrrolidinone (tech) 1-(3-Aminopropyl)-2- 2-(2- Hydrogen 12.5 pyrrolidinone (tech) Aminomethyl)phenylthio)benzyl alcohol 4-(Trifluoromethyl)benzylamine 2,5-Dimethoxyphenethylamine Hydrogen 12.5 4-(Trifluoromethyl)benzylamine 1-(1-Naphthyl)ethylamine Hydrogen 12.5 Veratryl amine 4-Phenylbutylamine Hydrogen 12.5 5-Amino-1-pentanol 2,5-Dimethoxyphenethylamine Hydrogen 12.5 5-Amino-1-pentanol 2-(2- Hydrogen 12.5 Aminomethyl)phenylthio)benzyl alcohol 2-(1-Cyclohexenyl)ethylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 12.5 2-(1-Cyclohexenyl)ethylamine 4-Fluorophenethylamine Hydrogen 12.5 2-(1-Cyclohexenyl)ethylamine 4-Phenylbutylamine Hydrogen 12.5 2-(1-Cyclohexenyl)ethylamine 2,5-Dimethoxyphenethylamine Hydrogen 12.5 2-(1-Cyclohexenyl)ethylamine 2-(2-Aminomethyl) Hydrogen 12.5 phenylthio)benzyl alcohol 1-Aminomethyl-1- 2,5-Dimethoxyphenethylamine Hydrogen 12.5 cyclohexanol, HCl 3-Fluorobenzylamine 2,5-Dimethoxyphenethylamine Hydrogen 12.5 4-Amino-1-butanol Hexetidine (mixture of isomers) Hydrogen 12.5 2-Ethoxybenzylamine Hexetidine (mixture of isomers) Hydrogen 12.5 cis-(−)-Myrtanylamine Cyclooctylamine Hydrogen 12.5 67.73 cis-(−)-Myrtanylamine 4-Methylcyclohexylamine Hydrogen 12.5 18.39 cis-(−)-Myrtanylamine 1-Adamantanamine Hydrogen 12.5 60.16 cis-(−)-Myrtanylamine 3,3-Diphenylpropylamine Methyl 12.5 22.32 Cyclooctylamine (+)-Isopinocampheylamine Hydrogen 12.5 57.83 Cyclooctylamine (+)-Bornylamine Hydrogen 12.5 100.00 Cyclooctylamine 1-Adamantanemethylamine Hydrogen 12.5 52.95 Cyclooctylamine 2,2-Diphenylamine Hydrogen 12.5 71.43 Cyclooctylamine cis-(−)-Myrtanylamine Hydrogen 12.5 84.56 Cyclooctylamine Cyclooctylamine Hydrogen 12.5 59.21 Cyclooctylamine Hexetidine (mixture of isomers) Hydrogen 12.5 Cyclooctylamine Aminodiphenylmethane Hydrogen 12.5 Cyclooctylamine Undecylamine Hydrogen 12.5 5.61 Cyclooctylamine 3,3-Diphenylpropylamine Methyl 12.5 53.92 Cyclooctylamine (+)-Isopinocampheylamine Methyl 12.5 Cyclooctylamine cis-(−)-Myrtanylamine Methyl 12.5 33.89 4-Chlorophenylalaninol Hexetidine (mixture of isomers) Hydrogen 12.5 (−)-Isopinocampheylamine 3,3-Diphenylpropylamine Hydrogen 12.5 23.68 (−)-Isopinocampheylamine (+)-Bornylamine Hydrogen 12.5 44.85 (−)-Isopinocampheylamine 2-Amino-1-propanol, d,1 Hydrogen 12.5 46.19 (−)-Isopinocampheylamine cis-(−)-Myrtanylamine Hydrogen 12.5 33.87 (−)-Isopinocampheylamine 2-Adamantanamine, HCl Hydrogen 12.5 24.29 (−)-Isopinocampheylamine Aminodiphenylmethane Hydrogen 12.5 48.35 Allylamine Hexetidine (mixture of isomers) Hydrogen 12.5 3-Ethoxypropylamine Hexetidine (mixture of isomers) Hydrogen 12.5 sec-Butylamine Dehydroabietylamine Hydrogen 12.5 2-Aminoheptane Dehydroabietylamine Hydrogen 12.5 Ethanolamine Hexetidine (mixture of isomers) Hydrogen 12.5 3-Methylbenzylamine 4-Phenylbutylamine Hydrogen 12.5 3-Methylbenzylamine 2,4-Dichlorophenethylamine Hydrogen 12.5 3-Methylbenzylamine Dehydroabietylamine Hydrogen 12.5 Piperonylamine Hexetidine (mixture of isomers) Hydrogen 12.5 Piperonylamine Dehydroabietylamine Hydrogen 12.5 2-Methoxyethylamine Dehydroabietylamine Hydrogen 12.5 4-Fluorophenethylamine Hexetidine (mixture of isomers) Hydrogen 12.5 3-o-Methyldopamine, HCl Hexetidine (mixture of isomers) Hydrogen 12.5 3-o-Methyldopamine, HCl Undecylamine Hydrogen 12.5 3-o-Methyldopamine, HCl Dehydroabietylamine Hydrogen 12.5 3-Fluorophenethylamine Hexetidine (mixture of isomers) Hydrogen 12.5 3-Fluorophenethylamine Dehydroabietylamine Hydrogen 12.5 2-Methoxyphenethylamine Hexetidine (mixture of isomers) Hydrogen 12.5 2-Methoxyphenethylamine Aminodiphenylmethane Hydrogen 12.5 34.67 2-Fluoroethylamine, HCl Hexetidine (mixture of isomers) Hydrogen 12.5 2-Amino-1-phenylethanol Hexetidine (mixture of isomers) Hydrogen 12.5 2-Amino-1-phenylethanol Dehydroabietylamine Hydrogen 12.5 2,5-Dimethoxyphenethylamine 2-Adamantanamine, HCl Hydrogen 12.5 22.18 2-(2-Chlorophenyl)ethylamine N-Allylcyclopentylamine Hydrogen 12.5 62.31 2-(2-Chlorophenyl)ethylamine Hexetidine (mixture of isomers) Hydrogen 12.5 3-Hydroxytyramine Hexetidine (mixture of isomers) Hydrogen 12.5 4- 2-Adamantanamine, HCl Hydrogen 12.5 28.34 (Trifluoromethoxy)benzylamine Geranylamine (+)-Bornylamine Hydrogen 12.5 Geranylamine 1,3,3-Trimethyl-6- Hydrogen 12.5 37.42 azabicyclo[3.2.1]octane Geranylamine 2-Ethylpiperidine Hydrogen 12.5 29.81 Geranylamine 1-Adamantanamine Hydrogen 12.5 16.63 Geranylamine N-Allylcyclopentylamine Hydrogen 12.5 74.86 Geranylamine Aminodiphenylmethane Hydrogen 12.5 57.93 Geranylamine Dehydroabietylamine Hydrogen 12.5 1-Adamantanemethylamine Decahydroquinoline Hydrogen 18.8 0 1-Adamantanemethylamine 1-Adamantanamine Hydrogen 18.8 0 2,2-Diphenylamine 2,3-Dimethylcyclohexylamine Hydrogen 18.8 23.60 2,2-Diphenylamine tert-Octylamine Hydrogen 18.8 19.29 2,2-Diphenylamine Decahydroquinoline Hydrogen 18.8 8.96 4-Methylbenzylamine Furfurylamine Hydrogen 25 13.46 4-Methylbenzylamine Benzylamine Hydrogen 25 17.07 4-Methylbenzylamine Hexetidine (mixture of isomers) Hydrogen 25 0 4-Methylbenzylamine Dehydroabietylamine Hydrogen 25 0 Cyclopentylamine Hexetidine (mixture of isomers) Hydrogen 25 0 Cyclopentylamine Dehydroabietylamine Hydrogen 25 0 Furfurylamine Furfurylamine Hydrogen 25 0 1-Methyl-3-phenylpropylamine Hexetidine (mixture of isomers) Hydrogen 25 0 1-Methyl-3-phenylpropylamine Undecylamine Hydrogen 25 0 1,2,3,4-Tetrahydro-1- Undecylamine Hydrogen 25 6.24 naphthylamine 1,2,3,4-Tetrahydro-1- Dehydroabietylamine Hydrogen 25 0 naphthylamine 2,3-Dimethylcyclohexylamine Undecylamine Hydrogen 25 0 2,3-Dimethylcyclohexylamine Dehydroabietylamine Hydrogen 25 0 Tyramine Hexetidine (mixture of isomers) Hydrogen 25 0 Tyramine Undecylamine Hydrogen 25 0 Tyramine Dehydroabietylamine Hydrogen 25 0 Tyramine cis-(−)-Myrtanylamine Methyl 25 0 2-Fluorobenzylamine Undecylamine Hydrogen 25 0 (R)-2-Amino-1-butanol Hexetidine (mixture of isomers) Hydrogen 25 0 3,3-Diphenylpropylamine (S)-(+)-1-Amino-2-propanol Hydrogen 25 0 3,3-Diphenylpropylamine 2-Ethylpiperidine Hydrogen 25 11.32 3,3-Diphenylpropylamine N-Allylcyclopentylamine Hydrogen 25 11.63 3,3-Diphenylpropylanime Aminodiphenylmethane Hydrogen 25 0 3,3-Diphenylpropylamine 3,5-Dimethylpiperidine (cis- Hydrogen 25 30.28 and trans-) 3,3-Diphenylpropylamine Allylcyclohexylamine Hydrogen 25 9.10 Propylamine Undecylamine Hydrogen 25 0 Phenethylamine Undecylamine Hydrogen 25 0 Tryptamine (S)-(+)-1-Amino-2-propanol Hydrogen 25 0 Tryptamine 2-Amino-2-methyl-1-propanol Hydrogen 25 0 Cyclohexylamine Undecylamine Hydrogen 25 0 Cyclohexylamine Dehydroabietylamine Hydrogen 25 0 (+)-Isopinocampheylamine Dehydroabietylamine Hydrogen 25 0 Benzylamine Hexetidine (mixture of isomers) Hydrogen 25 Benzylamine Undecylamine Hydrogen 25 3-Amino-1-propanol Dehydroabietylamine Hydrogen 25 0 2-Fluorophenethylamine 2-Fluorophenethylamine Hydrogen 25 0 2-Fluorophenethylamine Veratryl amine Hydrogen 25 0 2-Fluorophenethylamine 2,4-Dimethoxybenzylamine Hydrogen 25 0 2-Fluorophenethylamine 2-Amino-2-methyl-1-propanol Hydrogen 25 0 2-Fluorophenethylamine 4-Fluorophenethylamine Hydrogen 25 0 2-Fluorophenethylamine Hexetidine (mixture of isomers) Hydrogen 25 0 2-Fluorophenethylamine 1-(1-Naphthyl)ethylamine Hydrogen 25 0 2-Fluorophenethylamine 1-Adamantanemethylamine Methyl 25 3.21 2-Fluorophenethylamine cis-(−)-Myrtanylamine Methyl 25 4.89 b-Methylphenethylamine 4-Phenylbutylamine Hydrogen 25 0 b-Methylphenethylamine 2,4-Dichlorophenethylamine Hydrogen 25 0 b-Methylphenethylamine 1-(1-Naphthyl)ethylamine Hydrogen 25 0 4-Methoxyphenethylamine 1-Adamantanemethylamine Hydrogen 25 0 4-Methoxyphenethylamine 1-(3-Aminopropyl)-2- Hydrogen 25 0 pyrrolidinone (tech) 4-Methoxyphenethylamine Veratryl amine Hydrogen 25 0 4-Methoxyphenethylamine Undecylamine Hydrogen 25 0 4-Methoxyphenethylamine Dehydroabietylamine Hydrogen 25 0 Tetrahydrofurfurylamine Dehydroabietylamine Hydrogen 25 0 Amylamine 2-Fluorophenethylamine Hydrogen 25 0 Amylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 25 0 Amylamine 2,4-Dimethoxybenzylamine Hydrogen 25 0 3-Phenyl-1-propylamine 2-Fluorophenethylamine Hydrogen 25 3-Phenyl-1-propylamine 1-Adamantanemethylamine Hydrogen 25 3-Phenyl-1-propylamine 2,4-Dimethoxybenzylamine Hydrogen 25 3-Phenyl-1-propylamine Hexetidine (mixture of isomers) Hydrogen 25 3-Phenyl-1-propylamine 4-Phenylbutylamine Hydrogen 25 3-Phenyl-1-propylamine 2,4-Dichlorophenethylamine Hydrogen 25 3-Phenyl-1-propylamine Undecylamine Hydrogen 25 3-Phenyl-1-propylamine Dehydroabietylamine Hydrogen 25 2,2-Diphenylamine 4-(2-Aminoethyl)morpholine Hydrogen 25 2,2-Diphenylamine 1-(3-Aminopropyl)-2- Hydrogen 25 pyrrolidinone (tech) 2,2-Diphenylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 25 2,2-Diphenylamine 2,4-Dimethoxybenzylamine Hydrogen 25 2,2-Diphenylamine 4-(3-Aminopropyl)morpholine Hydrogen 25 2,2-Diphenylamine 4-Fluorophenethylamine Hydrogen 25 2,2-Diphenylamine Hexetidine (mixture of isomers) Hydrogen 25 2,2-Diphenylamine (S)-(−)-Cyclohexylethylamine Hydrogen 25 2,2-Diphenylamine 1-Adamantanemethylamine Methyl 25 5.84 1-(3-Aminopropyl)-2- 4-Phenylbutylamine Hydrogen 25 pyrrolidinone (tech) 4-(Trifluoromethyl)benzylamine 1-Adamantanemethylamine Hydrogen 25 4-(Trifluoromethyl)benzylamine tert-Amylamine Hydrogen 25 4-(Trifluoromethyl)benzylamine alpha-Methyltryptamine Hydrogen 25 6.06 4-(Trifluoromethyl)benzylamine 4-Phenylbutylamine Hydrogen 25 4-(Trifluoromethyl)benzylamine 2-(2-Aminomethyl) Hydrogen 25 5.13 phenylthio)benzyl alcohol 4-(Trifluoromethyl)benzylamine Undecylamine Hydrogen 25 4-(Trifluoromethyl)benzylamine (−)-3,4-Dihydroxynorephedrine Hydrogen 25 4-(Trifluoromethyl)benzylamine Dehydroabietylamine Hydrogen 25 Veratryl amine tert-Amylamine Hydrogen 25 5-Amino-1-pentanol 4-Phenylbutylamine Hydrogen 25 2-(1-Cyclohexenyl)ethylamine 2-Fluorophenethylamine Hydrogen 25 2-(1-Cyclohexenyl)ethylamine 1-Adamantanemethylamine Hydrogen 25 1-Aminomethyl-1- 4-Phenylbutylamine Hydrogen 25 cyclohexanol, HCl 3-Fluorobenzylamine 4-Phenylbutylamine Hydrogen 25 3-Fluorobenzylamine 2-(2- Hydrogen 25 Aminomethyl)phenylthio)benzyl alcohol 2,4-Dimethoxybenzylamine 1-Adamantanamine Hydrogen 25 2,4-Dimethoxybenzylamine Hexetidine (mixture of isomers) Hydrogen 25 2,4-Dimethoxybenzylamine Undecylamine Hydrogen 25 2,4-Dimethoxybenzylamine Dehydroabietylamine Hydrogen 25 2-Ethoxybenzylamine 1-Adamantanamine Hydrogen 25 2-Ethoxybenzylamine N-Phenylethyldiamine Hydrogen 25 2-Ethoxybenzylamine 2,4-Dichlorophenethylamine Hydrogen 25 2-Ethoxybenzylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 25 3.89 2-Ethoxybenzylamine Undecylamine Hydrogen 25 2-Ethoxybenzylamine Dehydroabietylamine Hydrogen 25 cis-(−)-Myrtanylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 25 cis-(−)-Myrtanylamine Hexetidine (mixture of isomers) Hydrogen 25 cis-(−)-Myrtanylamine Aminodiphenylmethane Hydrogen 25 cis-(−)-Myrtanylamine 2,4-Dichlorophenethylamine Hydrogen 25 cis-(−)-Myrtanylamine (S)-(−)-Cyclohexylethylamine Hydrogen 25 28.94 cis-(−)-Myrtanylamine Undecylamine Hydrogen 25 cis-(−)-Myrtanylamine (+)-Isopinocampheylamine Methyl 25 cis-(−)-Myrtanylamine Cyclooctylamine Methyl 25 24.92 Cyclooctylamine 2,3-Dimethylcyclohexylamine Hydrogen 25 50.55 Cyclooctylamine (S)-2-Amino-1-butanol Hydrogen 25 100.00 Cyclooctylamine 2-Adamantanamine, HCl Hydrogen 25 29.61 Cyclooctylamine 4-Phenylbutylamine Hydrogen 25 Cyclooctylamine 2-Chlorobenzylamine Hydrogen 25 Cyclooctylamine 2-Aminoindan, HCl Hydrogen 25 Cyclooctylamine Dehydroabietylamine Hydrogen 25 Cyclooctylamine 1-(1-Naphthyl)ethylamine Hydrogen 25 4.62 Cyclooctylamine 1-Adamantanemethylamine Methyl 25 14.20 2,3-Dimethoxybenzylamine Hexetidine (mixture of isomers) Hydrogen 25 2,3-Dimethoxybenzylamine Undecylamine Hydrogen 25 2,3-Dimethoxybenzylamine Dehydroabietylamine Hydrogen 25 4-Methylcyclohexylamine Hexetidine (mixture of isomers) Hydrogen 25 4-Methylcyclohexylamine Undecylamine Hydrogen 25 4-Methylcyclohexylamine Dehydroabietylamine Hydrogen 25 4-Fluorobenzylamine Dibenzylamine Hydrogen 25 27.98 trans-2- Cyclooctylamine Hydrogen 25 32.80 Phenylcyclopropylamine, HCl trans-2- 2-Adamantanamine, HCl Hydrogen 25 18.99 Phenylcyclopropylamine, HCl trans-2- 1-Adamantanamine Hydrogen 25 18.84 Phenylcyclopropylamine, HCl Thiomicamine Hexetidine (mixture of isomers) Hydrogen 25 (R)-1-Amino-2-propanol Hexetidine (mixture of isomers) Hydrogen 25 4-Chlorophenylalaninol 2,4-Dichlorophenethylamine Hydrogen 25 4-Chlorophenylalaninol Undecylamine Hydrogen 25 4-Chlorophenylalaninol Dehydroabietylamine Hydrogen 25 I-Leucinol Hexetidine (mixture of isomers) Hydrogen 25 I-Leucinol 2,4-Dichlorophenethylamine Hydrogen 25 I-Leucinol Dehydroabietylamine Hydrogen 25 (−)-Isopinocampheylamine 2-Methoxyphenethylamine Hydrogen 25 29.59 (−)-Isopinocampheylamine Undecylamine Hydrogen 25 Allylamine Dehydroabietylamine Hydrogen 25 3-Amino-1,2-propanediol Hexetidine (mixture of isomers) Hydrogen 25 3-Ethoxypropylamine 3,3-Diphenylpropylamine Hydrogen 25 3-Ethoxypropylamine Undecylamine Hydrogen 25 3-Ethoxypropylamine Dehydroabietylamine Hydrogen 25 sec-Butylamine 2,4-Dichlorophenethylamine Hydrogen 25 sec-Butylamine Undecylamine Hydrogen 25 2-Aminoheptane Hexetidine (mixture of isomers) Hydrogen 25 2-Aminoheptane 4-Phenylbutylamine Hydrogen 25 2-Aminoheptane 2,4-Dichlorophenethylamine Hydrogen 25 1-Naphthalenemethylamine Hexetidine (mixture of isomers) Hydrogen 25 1-Naphthalenemethylamine 4-Phenylbutylamine Hydrogen 25 1-Naphthalenemethylamine 2,4-Dichlorophenethylamine Hydrogen 25 1-Naphthalenemethylamine Undecylamine Hydrogen 25 Ethanolamine Dehydroabietylamine Hydrogen 25 Piperonylamine 4-Phenylbutylamine Hydrogen 25 1-Ethylpropylamine Hexetidine (mixture of isomers) Hydrogen 25 1-Ethylpropylamine Dehydroabietylamine Hydrogen 25 Isopropylamine Hexetidine (mixture of isomers) Hydrogen 25 4-Fluorophenethylamine 4-Phenylbutylamine Hydrogen 25 4-Fluorophenethylamine 2,4-Dichlorophenethylamine Hydrogen 25 4-Fluorophenethylamine Dehydroabietylamine Hydrogen 25 3-Fluorophenethylamine Undecylamine Hydrogen 25 2-Thiopheneethylamine 2-Adamantanamine, HCl Hydrogen 25 19.09 2-Methylcyclohexylamine (mix Hexetidine (mixture of isomers) Hydrogen 25 of cis and trans) 2-Methylcyclohexylamine (mix Dehydroabietylamine Hydrogen 25 of cis and trans) 2-Methoxyphenethylamine 2-Adamantanamine, HCl Hydrogen 25 26.77 2-Methoxyphenethylamine (−)-Isopinocampheylamine Hydrogen 25 31.95 2-Methoxyphenethylamine 1-Adamantanamine Hydrogen 25 24.38 2-Methoxyphenethylamine N-Allylcyclopentylamine Hydrogen 25 14.56 2-Methoxyphenethylamine 4-Phenylbutylamine Hydrogen 25 2-Methoxyphenethylamine Undecylamine Hydrogen 25 2-Methoxyphenethylamine Dehydroabietylamine Hydrogen 25 2-Fluoroethylamine, HCl Undecylamine Hydrogen 25 2-Fluoroethylamine, HCl Dehydroabietylamine Hydrogen 25 2-Aminoindan, HCl 2-Adamantanamine, HCl Hydrogen 25 17.72 2-Amino-1-phenylethanol Undecylamine Hydrogen 25 2,5-Dimethoxyphenethylamine (+)-Bornylamine Hydrogen 25 25.78 2,5-Dimethoxyphenethylamine Noradamantamine, HCl Hydrogen 25 11.73 2,5-Dimethoxyphenethylamine 1-Adamantanamine Hydrogen 25 12.57 2-(2-Chlorophenyl)ethylamine 4-Phenylbutylamine Hydrogen 25 2-(2-Chlorophenyl)ethylamine Undecylamine Hydrogen 25 2-(2-Chlorophenyl)ethylamine 1-(1-Naphthyl)ethylamine Hydrogen 25 2-(2- Hexetidine (mixture of isomers) Hydrogen 25 Aminomethyl)phenylthio)benzyl alcohol 2-(2- 4-Phenylbutylamine Hydrogen 25 Aminomethyl)phenylthio)benzyl alcohol 2-(2- Undecylamine Hydrogen 25 Aminomethyl)phenylthio)benzyl alcohol 1-Aminoindan Hexetidine (mixture of isomers) Hydrogen 25 1-Aminoindan Undecylamine Hydrogen 25 1-Aminoindan Dehydroabietylamine Hydrogen 25 1,3-Dimethylbutylamine Hexetidine (mixture of isomers) Hydrogen 25 1,3-Dimethylbutylamine Undecylamine Hydrogen 25 5.92 1,3-Dimethylbutylamine Dehydroabietylamine Hydrogen 25 (S)-(−)-Cyclohexylethylamine (−)-Isopinocampheylamine Hydrogen 25 19.31 (S)-(−)-Cyclohexylethylamine Hexetidine (mixture of isomers) Hydrogen 25 (S)-(−)-Cyclohexylethylamine Undecylamine Hydrogen 25 10.88 (S)-(−)-Cyclohexylethylamine Dehydroabietylamine Hydrogen 25 (S)-(−)-2-Amino-3-phenyl-1- Hexetidine (mixture of isomers) Hydrogen 25 propanol (S)-(−)-2-Amino-3-phenyl-1- Undecylamine Hydrogen 25 propanol (S)-(−)-2-Amino-3-phenyl-1- Dehydroabietylamine Hydrogen 25 propanol (1S,2S)-(+)-2-Amino-3- Hexetidine (mixture of isomers) Hydrogen 25 methoxy-1-phenyl-1-propanol Octadecylamine (+)-Bornylamine Hydrogen 25 Octadecylamine 1-Adamantanamine Hydrogen 25 Geranylamine 2,3-Dimethylcyclohexylamine Hydrogen 25 14.53 Geranylamine tert-Octylamine Hydrogen 25 15.22 Geranylamine 1-Adamantanemethylamine Hydrogen 25 4.37 Geranylamine Decahydroquinoline Hydrogen 25 31.79 Geranylamine Dibenzylamine Hydrogen 25 6.48 Geranylamine N-Butylbenzylamine Hydrogen 25 16.44 Geranylamine Cyclooctylamine Hydrogen 25 12.37 Geranylamine (−)-Isopinocampheylamine Hydrogen 25 8.95 Geranylamine 1-(1-Adamantyl)ethylamine, Hydrogen 25 32.95 HCl Geranylamine Undecylamine Hydrogen 25 Geranylamine 1-(1-Naphthyl)ethylamine Hydrogen 25 Amylamine 1-Adamantanamine Hydrogen 37.5 0 3-Phenyl-1-propylamine 3,3-Diphenylpropylamine Hydrogen 37.5 3-Phenyl-1-propylamine 2,2-Diphenylamine Hydrogen 37.5 3-Phenyl-1-propylamine 1-Adamantanamine Hydrogen 37.5 18.65 2,2-Diphenylamine 3,3-Diphenylpropylamine Hydrogen 37.5 2,2-Diphenylamine 2,2-Diphenylamine Hydrogen 37.5 5.56 2,2-Diphenylamine 1,3,3-Trimethyl-6- Hydrogen 37.5 8.67 azabicyclo[3.2.1]octane 2,2-Diphenylamine 1-Adamantanamine Hydrogen 37.5 58.10 4-(Trifluoromethyl)benzylamine tert-Octylamine Hydrogen 37.5 7.47 4-(Trifluoromethyl)benzylamine 138 Hydrogen 37.5 4-Methylbenzylamine 2-Fluorobenzylamine Hydrogen 50 22.10 4-Methylbenzylamine 4-Fluorobenzylamine Hydrogen 50 14.62 4-Methylbenzylamine alpha-Methyltryptamine Hydrogen 50 0 4-Methylbenzylamine Undecylamine Hydrogen 50 0 Cyclopentylamine Undecylamine Hydrogen 50 0 Furfurylamine 2-Fluorobenzylamine Hydrogen 50 0 Furfurylamine Benzylamine Hydrogen 50 0 Furfurylamine 4-Fluorobenzylamine Hydrogen 50 0 Furfurylamine alpha-Methyltryptamine Hydrogen 50 0 Furfurylamine Undecylamine Hydrogen 50 0 Furfurylamine Dehydroabietylamine Hydrogen 50 0 Furfurylamine Furfurylamine Hydrogen 50 0 3,4,5-Trimethoxybenzylamine 2-Fluorobenzylamine Hydrogen 50 0 3,4,5-Trimethoxybenzylamine Benzylamine Hydrogen 50 0 3,4,5-Trimethoxybenzylamine alpha-Methyltryptamine Hydrogen 50 0 3,4,5-Trimethoxybenzylamine Undecylamine Hydrogen 50 0 3,4,5-Trimethoxybenzylamine Dehydroabietylamine Hydrogen 50 0 1-Methyl-3-phenylpropylamine alpha-Methyltryptamine Hydrogen 50 0 1-Methyl-3-phenylpropylamine Octadecylamine Hydrogen 50 0 Cyclobutylamine Octadecylamine Hydrogen 50 0 Cyclobutylamine Undecylamine Hydrogen 50 0 Cyclobutylamine Dehydroabietylamine Hydrogen 50 0 1,2,3,4-Tetrahydro-1- Hexetidine (mixture of isomers) Hydrogen 50 0 naphthylamine 1,2,3,4-Tetrahydro-1- Aminodiphenylmethane Hydrogen 50 4.31 naphthylamine 1,2,3,4-Tetrahydro-1- alpha-Methyltryptamine Hydrogen 50 0 naphthylamine 1,2,3,4-Tetrahydro-1- 2-Methoxyphenethylamine Hydrogen 50 0 naphthylamine 2,3-Dimethylcyclohexylamine Hexetidine (mixture of isomers) Hydrogen 50 0 2,3-Dimethylcyclohexylamine Aminodiphenylmethane Hydrogen 50 3.64 2,3-Dimethylcyclohexylamine alpha-Methyltryptamine Hydrogen 50 0 Tyramine Furfurylamine Hydrogen 50 0 Tyramine 2-Fluorobenzylamine Hydrogen 50 4.07 Tyramine Benzylamine Hydrogen 50 0 Tyramine 2,4-Dichlorophenethylamine Hydrogen 50 0 2-Fluorobenzylamine Aminodiphenylmethane Hydrogen 50 0 2-Fluorobenzylamine 4-Phenylbutylamine Hydrogen 50 0 2-Fluorobenzylamine 2-Methoxyphenethylamine Hydrogen 50 0 2-Fluorobenzylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 2-Fluorobenzylamine 1,3-Dimethylbutylamine Hydrogen 50 0 2-Fluorobenzylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 0 HCl (R)-2-Amino-1-butanol Dehydroabietylamine Hydrogen 50 0 3,4-Dimethoxyphenethylamine Aminodiphenylmethane Hydrogen 50 0 3,4-Dimethoxyphenethylamine 4-Phenylbutylamine Hydrogen 50 0 3,4-Dimethoxyphenethylamine 2-Methoxyphenethylamine Hydrogen 50 0 3,4-Dimethoxyphenethylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 3,4-Dimethoxyphenethylamine 1,3-Dimethylbutylamine Hydrogen 50 0 3,3-Diphenylpropylamine Piperidine Hydrogen 50 0 3,3-Diphenylpropylamine 2,3-Dimethylcyclohexylamine Methyl 50 7.81 3,3-Diphenylpropylamine (−)-Isopinocamphenylamine Methyl 50 13.06 Propylamine (S)-(+)-1-Amino-2-propanol Hydrogen 50 0 Phenethylamine (S)-(+)-1-Amino-2-propanol Hydrogen 50 0 Phenethylamine 4-Phenylbutylamine Hydrogen 50 0 Phenethylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 Phenethylamine 1,3-Dimethylbutylamine Hydrogen 50 0 Phenethylamine 1-(1-Adamantyl)ethylamine Hydrogen 50 0 HCl Phenethylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 0 4-(2-Aminoethyl)morpholine 2-Amino-2-methyl-1-propanol Hydrogen 50 0 Cyclohexylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 exo-Aminonorbornane Benzylamine Hydrogen 50 0 (+)-Isopinocampheylamine Hexetidine (mixture of isomers) Hydrogen 50 0 (+)-Isopinocampheylamine Aminodiphenylmethane Hydrogen 50 5.07 (+)-Isopinocampheylamine 4-Phenylbutylamine Hydrogen 50 0 (+)-Isopinocampheylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 (+)-Isopinocampheylamine Undecylamine Hydrogen 50 0 Benzylamine 3,3-Diphenylpropylamine Hydrogen 50 Benzylamine 2-Amino-2-methyl-1-propanol Hydrogen 50 Benzylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 Benzylamine 2,4-Dichlorophenethylamine Hydrogen 50 3-Amino-1-propanol Undecylamine Hydrogen 50 0 2-Fluorophenethylamine 3,3-Diphenylpropylamine Hydrogen 50 0 2-Fluorophenethylamine 1-Adamantanemethylamine Hydrogen 50 0 2-Fluorophenethylamine 1-(3-Aminopropyl)-2- Hydrogen 50 0 pyrrolidinone (tech) 2-Fluorophenethylamine Decahydroquinoline Hydrogen 50 0 2-Fluorophenethylamine 1-Adamantanamine Hydrogen 50 24.34 2-Fluorophenethylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 2-Fluorophenethylamine Undecylamine Hydrogen 50 0 2-Fluorophenethylamine Dehydroabietylamine Hydrogen 50 0 2-Fluorophenethylamine 2-(1-Cyclohexenyl)ethylamine Methyl 50 0 2-Fluorophenethylamine Cyclooctylamine Methyl 50 5.81 b-Methylphenethylamine 3,3-Diphenylpropylamine Hydrogen 50 0 b-Methylphenethylamine tert-Octylamine Hydrogen 50 0 b-Methylphenethylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 50 0 b-Methylphenethylamine 2-Amino-2-methyl-1-propanol Hydrogen 50 0 b-Methylphenethylamine 4-Fluorophenethylamine Hydrogen 50 0 b-Methylphenethylamine Geranylamine Hydrogen 50 0 b-Methylphenethylamine 5-Methoxytryptamine Hydrogen 50 0 4-Methoxyphenethylamine 3,3-Diphenylpropylamine Hydrogen 50 0 4-Methoxyphenethylamine 2-Amino-2-methyl-1-propanol Hydrogen 50 0 4-Methoxyphenethylamine 2,4-Dichlorophenethylamine Hydrogen 50 0 4-Methoxyphenethylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 0 L-Methioninol Hexetidine (mixture of isomers) Hydrogen 50 0 Tetrahydrofurfurylamine 1-Adamantanemethylamine Hydrogen 50 0 Tetrahydrofurfurylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 50 0 Tetrahydrofurfurylamine 4-Fluorophenethylamine Hydrogen 50 0 Tetrahydrofurfurylamine Undecylamine Hydrogen 50 0 Amylamine 1-Adamantanemethylamine Hydrogen 50 0 Amylamine Hexetidine (mixture of isomers) Hydrogen 50 0 Amylamine Undecylamine Hydrogen 50 0 Amylamine Dehydroabietylamine Hydrogen 50 0 1-Adamantanemethylamine cis-(−)-Myrtanylamine Methyl 50 0 3-Phenyl-1-propylamine 4-(2-Aminoethyl)morpholine Hydrogen 50 3-Phenyl-1-propylamine 1-(3-Aminopropyl)-2- Hydrogen 50 pyrrolidinone (tech) 3-Phenyl-1-propylamine Veratryl amine Hydrogen 50 3-Phenyl-1-propylamine Aminodiphenylmethane Hydrogen 50 3-Phenyl-1-propylamine 2-(2- Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 2,2-Diphenylamine 2-Fluorophenethylamine Hydrogen 50 2,2-Diphenylamine 3,3-Diphenylpropylamine Methyl 50 2,2-Diphenylamine (+)-Isopinocampheylamine Methyl 50 2,2-Diphenylamine (+)-Bornylamine Methyl 50 2,2-Diphenylamine Cyclooctylamine Methyl 50 2,2-Diphenylamine (−)-Isopinocampheylamine Methyl 50 3.81 4-(Trifluoromethyl)benzylamine 4-(2-Aminoethyl)morpholine Hydrogen 50 4-(Trifluoromethyl)benzylamine 2-(1-Cyclohexenyl)ethylamine Hydrogen 50 4-(Trifluoromethyl)benzylamine Hexetidine (mixture of isomers) Hydrogen 50 4-(Trifluoromethyl)benzylamine 2,4-Dichlorophenethylamine Hydrogen 50 4-(Trifluoromethyl)benzylamine (S)-(−)-Cyclohexylethylamine Hydrogen 50 Veratryl amine 1-Adamantanemethylamine Hydrogen 50 Veratryl amine 2-(1-Cyclohexenyl)ethylamine Hydrogen 50 Veratryl amine 4-Fluorophenethylamine Hydrogen 50 Veratryl amine Hexetidine (mixture of isomers) Hydrogen 50 Veratryl amine 2,4-Dichlorophenethylamine Hydrogen 50 Veratryl amine (S)-(−)-Cyclohexylethylamine Hydrogen 50 Veratryl amine Undecylamine Hydrogen 50 Veratryl amine Dehydroabietylamine Hydrogen 50 Veratryl amine 1-(1-Naphthyl)ethylamine Hydrogen 50 5-Amino-1-pentanol 1-Adamantanemethylamine Hydrogen 50 5-Amino-1-pentanol Dibenzylamine Hydrogen 50 5-Amino-1-pentanol cis-(−)-Myrtanylamine Hydrogen 50 12.97 2-(1-Cyclohexenyl)ethylamine 2,4-Dimethoxybenzylamine Hydrogen 50 1-Aminomethyl-1- tert-Amylamine Hydrogen 50 cyclohexanol, HCl 1-Aminomethyl-1- 2-(2- Hydrogen 50 cyclohexanol, HCl Aminomethyl)phenylthio)benzyl alcohol 1-Aminomethyl-1- Undecylamine Hydrogen 50 cyclohexanol, HCl 1-Aminomethyl-1- 1-(1-Naphthyl)ethylamine Hydrogen 50 cyclohexanol, HCl 3-Fluorobenzylamine tert-Amylamine Hydrogen 50 3-Fluorobenzylamine Hexetidine (mixture of isomers) Hydrogen 50 3-Fluorobenzylamine Undecylamine Hydrogen 50 4-Amino-1-butanol Undecylamine Hydrogen 50 4-Amino-1-butanol Dehydroabietylamine Hydrogen 50 2,4-Dimethoxybenzylamine N-Phenylethyldiamine Hydrogen 50 2,4-Dimethoxybenzylamine Aminodiphenylmethane Hydrogen 50 2,4-Dimethoxybenzylamine 4-Phenylbutylamine Hydrogen 50 2,4-Dimethoxybenzylamine 2-Chlorobenzylamine Hydrogen 50 2,4-Dimethoxybenzylamine 2,4-Dichlorophenethylamine Hydrogen 50 2,4-Dimethoxybenzylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 50 2,4-Dimethoxybenzylamine 4- Hydrogen 50 (Trifluoromethoxy)benzylamine 2-Ethoxybenzylamine Aminodiphenylmethane Hydrogen 50 2-Ethoxybenzylamine 4-Phenylbutylamine Hydrogen 50 2-Ethoxybenzylamine 2-Chlorobenzylamine Hydrogen 50 2-Ethoxybenzylamine 2-Aminoindan, HCl Hydrogen 50 2-Ethoxybenzylamine 2,5-Dimethoxyphenethylamine Hydrogen 50 2-Ethoxybenzylamine 4- Hydrogen 50 (Trifluoromethoxy)benzylamine 2-Ethoxybenzylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 cis-(−)-Myrtanylamine 4-(2-Aminoethyl)morpholine Hydrogen 50 cis-(−)-Myrtanylamine 2-Fluorophenethylamine Hydrogen 50 cis-(−)-Myrtanylamine 1-(3-Aminopropyl)-2- Hydrogen 50 pyrrolidinone (tech) cis-(−)-Myrtanylamine Veratryl amine Hydrogen 50 cis-(−)-Myrtanylamine N-Butylbenzylamine Hydrogen 50 cis-(−)-Myrtanylamine 2,4-Dimethoxybenzylamine Hydrogen 50 cis-(−)-Myrtanylamine 1,2,3,4-Tetrahydropyridoindole Hydrogen 50 cis-(−)-Myrtanylamine 4-Phenylbutylamine Hydrogen 50 cis-(−)-Myrtanylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 50 3.91 cis-(−)-Myrtanylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 10.85 HCl cis-(−)-Myrtanylamine (R)-(−)-Cyclohexylethylamine Hydrogen 50 5.89 cis-(−)-Myrtanylamine Dehydroabietylamine Hydrogen 50 cis-(−)-Myrtanylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 cis-(−)-Myrtanylamine (+)-Bornylamine Methyl 50 4.04 Cyclooctylamine 4-Methylcyclohexylamine Hydrogen 50 4.55 Cyclooctylamine N-Phenylethyldiamine Hydrogen 50 Cyclooctylamine 4-(Hexacylamino)benzylamine Hydrogen 50 Cyclooctylamine 2,5-Dimethoxyphenethylamine Hydrogen 50 Cyclooctylamine 2,4-Dichlorophenethylamine Hydrogen 50 3.36 Cyclooctylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 50 9.15 Cyclooctylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 10.62 HCl Cyclooctylamine (S)-(−)-Cyclohexylethylamine Hydrogen 50 5.85 Cyclooctylamine (R)-(−)-Cyclohexylethylamine Hydrogen 50 Cyclooctylamine 4- Hydrogen 50 4.54 (Trifluoromethoxy)benzylamine 2-Adamantanamine, HCl cis-(−)-Myrtanylamine Hydrogen 50 49.73 4-Methylcyclohexylamine N-Phenylethyldiamine Hydrogen 50 4-Methylcyclohexylamine 4-Phenylbutylamine Hydrogen 50 4-Fluorobenzylamine N-Benzyl-2-phenethylamine Hydrogen 50 4-Fluorobenzylamine Hexetidine (mixture of isomers) Hydrogen 50 4-Fluorobenzylamine Undecylamine Hydrogen 50 4-Fluorobenzylamine Dehydroabietylamine Hydrogen 50 trans-2- Hexetidine (mixture of isomers) Hydrogen 50 Phenylcyclopropylamine, HCl trans-2- Undecylamine Hydrogen 50 Phenylcyclopropylamine, HCl trans-2- Dehydroabietylamine Hydrogen 50 Phenylcyclopropylamine, HCl (R)-1-Amino-2-propanol 4-(Hexacylamino)benzylamine Hydrogen 50 (R)-1-Amino-2-propanol Undecylamine Hydrogen 50 (R)-1-Amino-2-propanol Dehydroabietylamine Hydrogen 50 I-Leucinol Undecylamine Hydrogen 50 (−)-Isopinocampheylamine 2-Ethoxybenzylamine Hydrogen 50 27.27 (−)-Isopinocampheylamine Hexetidine (mixture of isomers) Hydrogen 50 (−)-Isopinocampheylamine 4-Phenylbutylamine Hydrogen 50 (−)-Isopinocampheylamine Dehydroabietylamine Hydrogen 50 (−)-Isopinocampheylamine 1-(1-Naphthyl)ethylamine Hydrogen 50 Allylamine 3,3-Diphenylpropylamine Hydrogen 50 Allylamine 2-Amino-1-propanol, d,1 Hydrogen 50 Allylamine Undecylamine Hydrogen 50 3-Amino-1,2-propanediol Dehydroabietylamine Hydrogen 50 3-Ethoxypropylamine 2,2-Diphenylamine Hydrogen 50 95.81 3-Ethoxypropylamine cis-(−)-Myrtanylamine Hydrogen 50 2-Aminoheptane 2-(2- Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 1-Naphthalenemethylamine Geranylamine Hydrogen 50 1-Naphthalenemethylamine Dehydroabietylamine Hydrogen 50 1-Aminopyrrolidine, HCl Hexetidine (mixture of isomers) Hydrogen 50 1-Aminopyrrolidine, HCl Undecylamine Hydrogen 50 1-Aminopyrrolidine, HCl Dehydroabietylamine Hydrogen 50 Ethanolamine 3,3-Diphenylpropylamine Hydrogen 50 3-Methylbenzylamine Geranylamine Hydrogen 50 3-Methylbenzylamine 5-Methoxytryptamine Hydrogen 50 Piperonylamine Aminodiphenylmethane Hydrogen 50 Piperonylamine 2,4-Dichlorophenethylamine Hydrogen 50 Piperonylamine 2-(2- Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol Isopropylamine Dehydroabietylamine Hydrogen 50 4-Fluorophenethylamine 2,4-Dimethoxybenzylamine Hydrogen 50 4-Fluorophenethylamine Aminodiphenylmethane Hydrogen 50 4-Fluorophenethylamine 2-(2- Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 4-Chloroamphetamine, HCl N-Allylcyclopentylamine Hydrogen 50 10.25 4-Chloroamphetamine, HCl Hexetidine (mixture of isomers) Hydrogen 50 4-Chloroamphetamine, HCl 4-Phenylbutylamine Hydrogen 50 4-Chloroamphetamine, HCl 2-Methoxyphenethylamine Hydrogen 50 4-Chloroamphetamine, HCl Undecylamine Hydrogen 50 4-Chloroamphetamine, HCl Dehydroabietylamine Hydrogen 50 3-Fluorophenethylamine (−)-Isopinocampheylamine Hydrogen 50 3-Fluorophenethylamine 1-Adamantamine Hydrogen 50 8.59 3-Fluorophenethylamine 4-Phenylbutylamine Hydrogen 50 2-Methylcyclohexylamine (mix Undecylamine Hydrogen 50 of cis and trans) 2-Methoxyphenethylamine 3,3-Diphenylpropylamine Hydrogen 50 2-Methoxyphenethylamine (+)-Bornylamine Hydrogen 50 2-Methoxyphenethylamine tert-Octylamine Hydrogen 50 20.46 2-Methoxyphenethylamine 1-Adamantanemethylamine Hydrogen 50 2-Methoxyphenethylamine Dibenzylamine Hydrogen 50 2-Methoxyphenethylamine N-Butylbenzylamine Hydrogen 50 5.20 2-Methoxyphenethylamine 1,3,3-Trimethyl-6- Hydrogen 50 8.59 azabicyclo[3.2.1]octane 2-Methoxyphenethylamine N-Phenylethyldiamine Hydrogen 50 2-Methoxyphenethylamine 2,4-Dichlorophenethylamine Hydrogen 50 2-Methoxyphenethylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 50 2-Methoxyphenethylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 3.61 HCl 2-Aminoindan, HCl (+)-Bornylamine Hydrogen 50 2-Aminoindan, HCl Noradamantamine, HCl Hydrogen 50 7.43 2-(2-Chlorophenyl)ethylamine N-Phenylethyldiamine Hydrogen 50 2-(2-Chlorophenyl)ethylamine Aminodiphenylmethane Hydrogen 50 2-(2-Chlorophenyl)ethylamine 2,4-Dichlorophenethylamine Hydrogen 50 2-(2-Chlorophenyl)ethylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 HCl 2-(2-Chlorophenyl)ethylamine Dehydroabietylamine Hydrogen 50 2-(2- 2-Methoxyphenethylamine Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 2-(2- 2,5-Dimethoxyphenethylamine Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 2-(2- 2-(2-Chlorophenyl)ethylamine Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 2-(2- 1-(1-Adamantyl)ethylamine, Hydrogen 50 Aminomethyl)phenylthio)benzyl HCl alcohol 2-(2- Dehydroabietylamine Hydrogen 50 Aminomethyl)phenylthio)benzyl alcohol 1-Aminoindan 4-Phenylbutylamine Hydrogen 50 1-Aminoindan 2,4-Dichlorophenethylamine Hydrogen 50 1,3-Dimethylbutylamine 4-Phenylbutylamine Hydrogen 50 (S)-(−)-Cyclohexylethylamine Aminodiphenylmethane Hydrogen 50 (S)-(−)-Cyclohexylethylamine 4-Phenylbutylamine Hydrogen 50 (S)-(−)-Cyclohexylethylamine 2,4-Dichlorophenethylamine Hydrogen 50 (S)-(−)-Cyclohexylethylamine 1-(1-Adamantyl)ethylamine, Hydrogen 50 HCl (1S,2S)-(+)-2-Amino-3- Dehydroabietylamine Hydrogen 50 methoxy-1-phenyl-1-propanol Octadecylamine 2-Adamantanamine, HCl Hydrogen 50 3-Hydroxytyramine (1R,2S)-(−)-2-Amino-1,2- Hydrogen 50 diphenylethanol 3-Hydroxytyramine Dehydroabietylamine Hydrogen 50 Geranylamine 3,3-Diphenylpropylamine Hydrogen 50 Geranylamine N-Phenylethyldiamine Hydrogen 50 Geranylamine Hexetidine (mixture of isomers) Hydrogen 50 Geranylamine 2-Thiopheneethylamine Hydrogen 50 Geranylamine 2-Methoxyphenethylamine Hydrogen 50 Geranylamine 2,5-Dimethoxyphenethylamine Hydrogen 50 Geranylamine 2,4-Dichlorophenethylamine Hydrogen 50 Geranylamine 2-(2-Chlorophenyl)ethylamine Hydrogen 50 2-Fluorophenethylamine 2,3-Dimethylcyclohexylamine Methyl >50 2.07 4-(Trifluoromethyl)benzylamine 2,3-Dimethylcyclohexylamine Hydrogen >50 8.20 4-(Trifluoromethyl)benzylamine 1-Adamantanamine Hydrogen >50 32.02 5-Aminoquinoline exo-Aminonorbornane Hydrogen >50 17.87

[0104] TABLE 3 Compounds Synthesized in Larger Quantities for Further in vitro Evaluations Amount, Yields, Cmpd # Name Structure mg % 1 N-(4-Methylphenyl)-N′- (furfuryl)ethane-1,2-diamine

23 25 2 N-(4-Methylphenyl)-N′- (benzyl)ethane-1,2-diamine

27 29 3 N-[1-(1,2,3,4-Tetrahydro- naphthalene)-N′-(undecenyl)- ethane-1,2-diamine

11 10 4 N-[2-(3,4-Dimethoxy- phenyl)-ethyl-N′-(1- methyladamantyl)-ethane- 1,2-diamine

13 11 5 N-[2-(3,4-Dimethoxy- phenyl)ethyl-N′-(norbornyl)- ethane-1,2-diamine

9 8 6 N-(1-Adamantylmethyl)-N′- (3,3 -diphenylpropyl)propane- 1,2-diamine

55 36 7 N-(1-Adamantylmethyl)-N′- (3,3-diphenylpropyl)ethane- 1,2-diamine

28 22 8 N-[2-(Cyclohexen-1-yl)ethyl]- N-(3,3-diphenylpropyl)- propane-1,2-diamine

46 37 10 N-(−)-cis-Myrtanyl-N′-(3,3- diphenylpropyl)ethane-1,2- diamine

14 11 11 N-Cyclooctyl-N′-(3,3- diphenylpropyl)ethane-1,2- diamine

22 18 13 N-Allyl-N-cyclopentyl-N-(3,3- diphenylpropyl)ethane-1,2- diamine

33 27 14 N-(3,3-Diphenylpropyl)-N′- exo-(2-norborny)ethane-1,2- diamine

17 16 15 1-{2-[N-(3,3-Diphenylpropyl)]- aminoethyl}-3,5-dimethyl- piperidine

6.2 5 17 N-2-(2-Methoxyphenyl)ethyl- N′-(3,3-diphenylethyl)ethane- 1,2-diamine

50 40 21 N-(3,3-Diphenylpropyl)-N′- (1S)-(1-ethylcyclohexane)- ethane-1,2-diamine

5 4 22 N-(3,3-Diphenylpropyl)-N′- (1R)-(1-ethylcyclohexane)- ethane-1,2-diamine

21 17 23 N-Allyl-N-cyclohexyl-N-(3,3- diphenylpropyl)ethane-1,2- diamine

6 5 24 N-2-(2-Methoxyphenyl)ethyl- N′-(4-fluorophenylethyl)- ethane-1,2-diamine

10 9 27 N-(3-Phenylpropyl)-N′-(1- adamantyl)ethane-1,2- diamine

11 10 28 N-(3-Phenylpropyl)-N′-(4- fluorophenyl)ethane-1,2- diamine

11 10 29 N-(2,2-Diphenylethyl)-N′-(2,3- dimethylcylcohexyl)ethane- 1,2-diamine

4.5 4 31 N-(2,2-Diphenylethyl)-N′-(1S)- (1-ethylcyclohexane)-ethane- 1,2-diamine

24 20 32 N-(2,2-Diphenylethyl)-N′-(R)- (+)-

58 48 33 N-(2,2-Diphenylethyl)-N′- (1,1,3,3-tetramethylbutyl)- ethane-1,2-diamine

11 9 34 N-(2,2-Diphenylethyl)-N′-(1- methyladamantyl)ethane-1,2- diamine

6.8 6 35 N-(2,2-Diphenylethyl)-N′- {1,1,3-trimethyl-6-azabicyclo- [3.2.1]octyl}ethane-1,2- diamine

38 30 36 N-{2-[N′-(2,2-Diphenylethyl)]- aminoethyl}- decahydroquinoline

28 24 37 N-(2,2-Diphenylethyl)-N′-(−)- cis-(myrtanyl)ethane-1,2- diamine

54 38 38 N-(−)-cis-(Myrtanyl)-N′-(2,2- diphenylethyl)propyl-1,2- diamine

39 30 40 N-(2,2-Diphenylethyl)-N′-(1R, 2R, 3R, 5S)-(−)-isopinocam- pheylethane-1,2-diamine

33 23 41 N-(−)-cis-(Myrtanyl)-N′-(2,3- dimethylcyclohexyl)ethane- 1,2-diamine

66 62 42 N-(3,3-Diphenylpropyl)-N′(−)- cis-myrtanylethane-1,2- diamine

11 9 43 N-(−)-cis-Myrtanyl-N′-(1S,2S, 3S,5R)-(+)- isopinocampheylethane-1,2- diamine

31 27 47 N-(−)-cis-Myrtanyl-N′-(1R,2R, 3R,5S)-(−)- isopinocampheylethane-1,2- diamine

42 33 51 N-(Cyclooctyl)-N′-(2,3- dimethylcyclohexyl)ethane- 1,2-diamine

5.1 2 52 N-(Cyclooctyl)-N′-(3,3- diphenylpropyl)ethane-1,2- diamine

20 18 53 N-Cyclooctyl-N′-(1S,2S,3S, 5R)-(+)-isopinocampheyl- ethane-1,2-diamine

7.4 7 54 N-Cyclooctyl-N′-(R)-(+)- bornylethane-1,2-diamine

17 16 55 N-(Cyclooctyl)-N′-(1- methyladamantyl)ethane-1,2- diamine

7 6 56 N-(Cyclooctyl)-N′-(2S)-[2-(1- hydroxybutyl)]ethane-1,2- diamine

1.1 1 57 N-(−)-cis-Myrtanyl-N′- (cyclooctyl)ethane-1,2- diamine

18 18 58 N-(Cyclooctyl)-N′-(2- adamantyl)ethane-1,2- diamine

25 23 59 N-(Cyclooctyl)-N′-(1R,2R, 3R,5S)-(−)- isopinocampheylethane-1,2- diamine

15 14 61 N-(Cyclooctyl)-N′-[1-ethyl-(1- naphthyl)]ethane-1,2-diamine

16 14 62 N-(−)-cis-Myrtanyl-N′-(1S)-(1- ethylcyclohexane)ethane-1,2- diamine

48 46 63 N-(Cyclooctyl)-N′-trans-(2- phenylcyclopropyl)ethane- 1,2-diamine

47 46 64 N-(2-Adamantyl)-N′-trans-(2- phenylcyclopropyl)ethane- 1,2-diamine

49 46 65 N-(1-Adamantyl)-N′-trans-(2- phenylcyclopropyl)ethane- 1,2-diamine

18 16 66 N-(3,3-Diphenylpropyl)-N′- (1R,2R,3R,5S)-(−)- isopinocampheylethane-1,2- diamine

2.3 2 68 N-(+/−)-[2-(1-Hydroxybutyl)]- N′-(1R,2R,3R,5S)-(−)- isopinocampheylethane-1,2- diamine

0.8 1 71 N-(1,1-Diphenylmethyl)-N′- (1R,2R,3R,5S)-(−)- isopinocampheylethane-1,2- diamine

2.9 2 73 N-(2-Adamantyl)-N′-[2-(2- methoxyphenyl)ethyl]ethane- 1,2-diamine

21 19 76 N-Allyl-N-cyclopentyl-N′-[2-(2- methoxyphenyl)ethyl]ethane- 1,2-diamine

8 7 77 N-(1,1-Diphenylmethyl)-N′-[2- (2-methoxyphenyl)- ethyl]ethane-1,2-diamine

32 27 78 N-2-Adamantyl-N′-2,3- dihydro-1H-inden-2-yl- ethane-1,2-diamine

4.3 3 79 N-[2-(2,5-Dimethoxyphenyl)- ethyl]-N′-(R)-(+)- bornylethane-1,2-diamine

59 49 103 N,N′-Bis(cyclooctyl)ethane- 1,2-diamine

6.3 4 107 N-(2,2-Diphenylethyl)-N-(3- ethoxypropyl)ethane-1,2- diamine

58 52 109 N-Geranyl-N′-(2- adamanthyl)ethane-1,2- diamine

27 24 111 N-[2-(N′-Geranyl)aminoethyl]- 2-ethylpiperidine

24 24 116 N-Geranyl-N′-allyl-N′- (cyclopentyl)ethane-1,2- diamine

45 42 117 N-Geranyl-N′-(1,1-diphenyl- methyl)ethane-1,2-diamine

24 20 118 N-2-(2-Chlorophenyl)ethyl-N′- allyl-N′-(cyclopentyl)ethane- 1,2-diamine

6.4 6 119 N-2-(2-Chlorophenyl)ethyl- N′-[2-(3-fluorophenyl)- ethyl]ethane-1,2-diamine

30 27 125 N,N′-bis-(−)-cis- Myrtanylpropane-1,2-diamine

41 35 134 N-[2-(N′-2,2-Diphenylethyl)- aminoethyl]-(−)-3,4- dihydroxynorephedrine

20 15 151 N-[2-(2-Methoxy)phenylethyl]- N′-(1R,2R,3R,5S)-(−)- isopinocampheyl-ethane-1,2- diamine

67 60 164 N¹-[2-(4-fluorophenyl)ethyl]- N²-[2-(4-Methoxy) phenylethyl)-1-phenylethane- 1,2-diamine

94 73 165 N1-[2-(4-fluorophenyl)ethyl]- N2-(3-Phenylpropyl)-1- phenylethane-1,2-diamine

23 19

[0105] Formulations

[0106] Therapeutics, including compositions containing the substituted ethylene diamine compounds of the present invention, can be prepared in physiologically acceptable formulations, such as in pharmaceutically acceptable carriers, using known techniques. For example, a substituted ethylene diamine compound is combined with a pharmaceutically acceptable excipient to form a therapeutic composition.

[0107] The compositions of the present invention may be administered in the form of a solid, liquid or aerosol. Examples of solid compositions include pills, creams, soaps and implantable dosage units. Pills may be administered orally. Therapeutic creams and anti-mycobacteria soaps may be administered topically. Implantable dosage units may be administered locally, for example, in the lungs, or may be implanted for systematic release of the therapeutic composition, for example, subcutaneously. Examples of liquid compositions include formulations adapted for injection intramuscularly, subcutaneously, intravenously, intraarterially, and formulations for topical and intraocular administration. Examples of aerosol formulations include inhaler formulations for administration to the lungs.

[0108] A sustained release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid/base hydrolysis, or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. The sustained release matrix is chosen desirably from biocompatible materials, including, but not limited to, liposomes, polylactides, polyglycolide (polymer of glycolic acid), polylactide co-glycolide (coplymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipds, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. A preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide.

[0109] The dosage of the composition will depend on the condition being treated, the particular composition used, and other clinical factors, such as weight and condition of the patient, and the route of administration. A suitable dosage may range from 100 to 0.1 mg/kg. A more preferred dosage may range from 50 to 0.2 mg/kg. A more preferred dosage may range from 25 to 0.5 mg/kg. Tablets or other forms of media may contain from 1 to 1000 mg of the substituted ethylene diamine. Dosage ranges and schedules of administration similar to ethambutol or other anti-tuberculosis drugs may be used.

[0110] The composition may be administered in combination with other compositions and procedures for the treatment of other disorders occurring in combination with mycobacterial disease. For example, tuberculosis frequently occurs as a secondary complication associated with acquired immunodeficiency syndrome (AIDS). Patients undergoing AIDS treatment, which includes procedures such as surgery, radiation or chemotherapy, may benefit from the therapeutic methods and compositions described herein.

[0111] The following specific examples will illustrate the invention as it applies to the particular synthesis of the substituted ethylene diamine compounds, and the in vitro and in vivo suppression of the growth of colonies of M. tuberculosis. It will be appreciated that other examples, including minor variations in chemical procedures, will be apparent to those skilled in the art, and that the invention is not limited to these specific illustrated examples.

EXAMPLE I Generating the Ethylene Diamine Library

[0112] The Rink-acid resin was obtained from NOVABIOCHEM® Inc., San Diego, Calif. Solvents: acetonitrile, dichloromethane, dimethylformamide, ethylenedichloride, methanol and tetrahydrofuran were purchased from ALDRICH®, Milwaukee, Wis., and used as received. All other reagents were purchased from SIGMA-ALDRICH®, West Monroe Highland, Ill. Solid phase syntheses were performed on a QUEST® 210 Synthesizer, from ARGONAUT TECHNOLOGIES®, Foster City, Calif., with the aid of combinatorial chemistry equipment, from WHATMAN® POLYFILTRONICS® (Kent, England; Rockland, Mass.) and ROBBINS SCIENTIFIC®, Sunnyvale, Calif. Evaporation of solvents was done using SPEEDVAC® AES, from SAVANT®, Holbrook, N.Y. All necessary chromatographic separations were performed on a WATERS' ALLIANCE HT SYSTEM®, Milford, Mass. Analytical thin-layer chromatography was performed on MERCK® silica gel 60F₂₅₄ plates, purchased from SIGMA-ALDRICH®, West Monroe Highland, Ill.

[0113] The activation of the Rink-acid resin, the addition of the first amine, and the acylation step were carried out in 10 ml tubes using the QUEST® 210 Synthesizer. The addition of the second amine, the reduction with Red-AL, and the cleavage from the solid support were carried out in 96-deep (2 ml) well, chemically resistant plates.

[0114] A. Activation of the Rink-Acid Resin

[0115] The Rink-acid resin had a coverage of 0.43-0.63 mmol of linker per gram resin. Four to five grams of this resin were suspended in 80 ml of a 2:1 mixture of dichloromethane and tetrahydrofuran (THF), and distributed into ten, 10 ml tubes, with 8 ml of resin suspension per tube. Each suspension was filtered and washed twice with THF. A solution of triphenylphosphine (3.80 g, 14.5 mmol) in 30 ml of THF was prepared, and 3 ml of this solution was added to each tube, followed by the addition of 3 ml of a solution of hexachloroethane in THF (3.39 g/14.3 mmol hexachloroethane in 30 ml THF). After agitation for six hours at room temperature, each activated resin was washed twice with THF and twice with dichloromethane.

[0116] B. Addition of the First Amine

[0117] Each tube, containing the activated rink resin, was charged with 3 ml of dichloroethane, 0.3 ml (1.74 mmol) N₁N-diisopropylethylamine (EtN(iPr)₂) and the corresponding amine (around 1 mmol). If the selected amine was a solid at room temperature, it was added as a solution, or a suspension in DMF. Enough dichloroethane was added to each tube for a final volume of 8 ml. The reaction mixture was heated at 45° C. for 6-8 hours. The resins were filtered, washed with a 2:1 mixture of dichloromethane and methanol (1×8 ml), then with methanol (2×8 ml), and then dried under argon for 10 minutes.

[0118] C. Acylation with the Halo-Acylchloride

[0119] a. Acylation with Chloroacetyl Chloride. Each resin was prewashed with THF (2×8 ml), and then charged with THF (8 ml), pyridine (0.3 ml, 3.67 mmole) and chloroacetyl chloride (0.25 ml, 2.5 mmole). The reaction mixture was stirred for 8 hours at 45° C., and then for 6-8 hours at room temperature. Each resin was filtered, washed with a 2:1 mixture of dichloromethane/methanol (1×8 ml), methanol (2×8 ml) and THF (2×8 ml). The acylation was repeated using the same loading of reagents, but a shorter reaction time of 4 hours at 45° C., and 2 hours at room temperature. Each resin was then filtered, washed with a 2:1 mixture of dichloromethane and methanol (1×8 ml), and then with methanol (3×8 ml). Each resin was dried under argon for 10 minutes. Each resin was then transferred into a vial and dried in a desiccator under vacuum for 1 hour.

[0120] b. Acylation with α-Phenyl-α-Chloroacetyl Chloride. The same procedure set out for the acylation with chloroacetyl chloride was used. A 2.5 mmol excess of α-phenyl-α-chloroacetyl chloride, relative to mmol amount of linker in the rink-acid resin, was used.

[0121] c. Acylation with α-Halo-α-Methyl; α-Halo-α-Ethyl and α-Halo-α-Butylacetyl Bromide. A 1:1:1 mixture (by volume) of the α-bromoproponyl bromide (R₄=Me), α-bromobutyryl bromide (R₄=Et), and α-bromohexanoyl bromide (R₄=Bu) was used to give a molar ratio of 0.52:0.56:0.42 (in nunols). This resulted in a molar excess of 1.65, 1.75 and 1.31, respectively, if the original coverage of the resin was 0.63 mmol/g (0.5 g resin per tube), and 2.4, 2.6 and 1.9 if the original coverage of the resins was 0.43 mmol/g (0.5 g resin per tube).

[0122] d. Acylation with α-Chloro-α-Methyl Acetic acid. Each resin was prewashed with dichloromethane. Each tube was charged with 3 ml of a solution of PyBrop (0.29 g, 0.62 mmole) in dichloromethane, a solution of the α-chloro-α-methylacetic acid (0.095 g, 0.62 mmole) in 3 ml of DMF, and EtN(iPr)₂ (0.2 ml, 1.2 mmole). Each reaction mixture was allowed to react for 16-18 hours at room temperature. Each resin was then filtered, washed with dichcloromethane (2×8 ml) and methanol (2×8 ml), and the acylation was repeated. Each resin was then filtered, washed with dichloromethane (2×8 ml), methanol (3×8 ml), and dried under argon for about 10 minutes. Each resin was transferred into a vial, and dried in a desiccator under vacuum for one hour.

[0123] D. Addition of the Second Amine

[0124] Ten, or thirty prepared α-haloacetyl amide resins from the first three steps were pooled together, leaving 0.05-0.10 gram of each individual resin for necessary deconvolutions. A suspension of the pooled resin mixture in 100 ml of a 2:1 mixture of dichloromethane and THF was distributed into one, two or three, 96-well reaction plates. For one reaction plate, 1.7 to 2.0 grams of resin were used. For two reaction plates, 3.0 to 3.3 grams of resin were used, and for three reaction plates, 4.7 to 5.0 grams of resin were used. The distributed suspension was then filtered using a filtration manifold, a small lightweight manifold that is generally used for drawing solvents and reagents from the chambers of the 96-well reaction plates. The reaction plates were transferred into COMBICLAMPS® (Huntington, W.Va.), and 10% EtN(iPr)₂ in DMF was added at 0.2 ml per well (0.21 mmole of EtN(iPr)₂ per well), followed by the addition of a 11.0M solution of the appropriate amine from the corresponding master plate, 0.1 ml per well (0.1 mmole amine per well). The COMBICLAMPS® are used to accommodate 96-well reaction plates during synthesis, allowing for the addition of reagents into the plates, and a proper sealing that maintains reagents and solvents for hours at elevated temperatures. These clamps consist of a top and bottom cover provided with changeable, chemically resistant sealing gaskets. They are designed to accommodate 96-well reaction plates between the top and bottom covers. The reaction plates were sealed and kept in an oven at 70-75° C. for 16 hours. After cooling to room temperature, the resins were filtered, washed with a 1:1 mixture of DCM/methanol (1×1 ml), methanol (2×1 ml), and then dried in a desiccator under vacuum for 2 hours.

[0125] E. Reduction with Red-Al

[0126] The reaction plates were placed into COMBICLAMPS®. A 1:6 mixture of Red-Al (65+w % in toluene) and THF was added, at 0.6 ml per well (0.28 mmole of Red-Al per well), and allowed to react for 4 hours. Each resin was then filtered, washed with THF (2×1 ml), and methanol (3×1 ml). The addition of methanol should proceed with caution. Each resin was then dried under vacuum.

[0127] F. Cleavage of Final Ethylene Diamine Compound

[0128] This step was carried out using a cleavage manifold, a Teflon coated aluminum, filter/collection vacuum manifold, designed for recovering cleavage products from the reaction plates into collection plates. The manifold is designed to ensure that the filtrate from each well is directed to a corresponding well in a receiving 96-well collection plate. The reaction plates (placed on the top of the collection plates in this manifold) were charged with a 10:85:5 mixture of TFA, dichloromethane, and methanol (0.5 ml of mixture per well). After fifteen minutes, the solutions were filtered and collected into proper wells on the collection plates. The procedure was repeated. Solvents were evaporated on a SPEED VAC®, Holbrook, N.Y., and the residual samples (TFA salts) were tested without further purification.

EXAMPLE II Deconvolution Example

[0129] Deconvolution of the active wells was performed by re-synthesis of discrete compounds, from the archived α-haloacetyl amide resins (10 resins, 0.05-0.10 g each), which were set aside at the end of the acylation step before the pooling. Each resin was assigned a discrete column (1, or 2, or 3, etc., see the template) in a 96 well filterplate, and was divided between X rows (A, B, C, etc), where X is the number of hits discovered in the original screening plate. To each well, in a row, a selected N2 (R₃R₂NH) hit amine (0.1 mmol), DMF (180 ml) and EtNiPr₂ (20 ml) were added: the first selected amine was added to the resins in the row “A”, the second amine—to the resins in the row “B”, the third amine—to the resins in the row “C”, etc. A lay-out of a representative 96-well filter plate is shown in Table 4.

[0130] The reaction plates were sealed and kept in an oven at 70-75° C. for 16 hours. After cooling to room temperature, the resins were filtered, washed with a 1:1 mixture of DCM and methanol (1×1 ml), methanol (2×1 ml), and dried in desiccator under vacuum for 2 h. Reduction and cleavage were performed according to steps 5 and 6 in the original synthetic protocol. The product wells from the cleavage were analyzed by ESI-MS (Electro Spray Ionization Mass Spectroscopy) to ensure the identity of the actives, and were tested in the same Luc and MIC assays. TABLE 4 Lay-Out of Representative 96-Well Filter Plate A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 Selected amine N2, Added to A1-A10 B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 Selected amine N2, Added to B1-B10 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 Selected amine N2, Added to C1-C10 D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 Selected amine N2, Added to D1-D10 E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 Selected amine N2, Added to E1-E10 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Selected amine N2, Added to F1- F10 G1 G2 G3 G4 G5 G6 G7 G8 G9 G10 Selected amine N2, Added to G1-G10 H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 Selected amine N2, Added to H1-H10 *X* selected Amines N2 to be added on the step 4 Resin Resin Resin Resin Resin Resin Resin Resin Resin Resin Individual #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 Resins #1-10, preloaded with proper amine N1.

EXAMPLE III Solid-Phase Synthesis of Selected Substituted Ethylenediamine Compounds Using the QUEST® 210 Synthesizer

[0131] The solid-phase protocol described above in Example I was applied to the scaled-up synthesis of the selected substituted ethylene diamine compounds. Here, all reaction steps, from the activation of the Rink-acid resin to the cleavage of the final product, were carried out using the QUEST® instrument only, which allowed for the simultaneous syntheses of twenty parallel reactions. Purification of all crude samples was done by HPLC to yield desirable products in purity greater than 90%. Table 3 lists the scale-ups of substituted ethylene diamines. Here, the synthesis of one of the active compounds, N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine is described below as an example.

[0132] The Preparation of N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine (compound 109) is set forth in FIG. 12.

[0133] 1. Activation of the Rink-acid resin. Synthesis of Rink-Cl resin. Rink-acid resin, coverage (linker) of 0.43 to 0.63 mmol/g (0.8 g, 0.5 mmol), was placed into one of the 10 ml tubes of QUEST® 210 Synthesizer, and washed twice with THF. A solution of triphenylphosphine (0.380 g, 1.45 mmol) in THF (3 ml) was added, followed by the addition of a solution of hexachloroethane (0.4 g, 1.43 mmol) in THF (3 ml). THF was added up to the volume of the tube (approximately 2 ml). After 6 hours, the resin was filtered, washed with THF (2×8 ml) and dichloromethane (2×8 ml).

[0134] 2. Addition of the first amine. Synthesis of resin attached geranylamine. The tube with activated resin was charged with 3 ml of dichloroethane, EtN(iPr)₂, (0.3 ml, 1.74 mmol), and geranylamine (0.230 g, 1.5 mmol). Dichloroethane was added to a volume of 8 ml. The reaction was carried for 8 hours at 45° C., and for 6-8 hours at room temperature. Geranylamine loaded resin was filtered, washed with a 2:1 mixture of dichloromethane and methanol (1×8 ml), then with methanol (2×8 ml), and suck dried for 10 minutes under argon.

[0135] 3. Acylation with chloroacetyl chloride. Synthesis of resin attached N-Geranyl-α-chloroacetamide. The resin was prewashed with THF (2×8 ml). The tube was charged with 8 ml of THF, pyridine (0.3 ml, 3.67 mmol), and chloroacetyl chloride (0.2 ml, 2.5 mmol), and allowed to stir for 8 h at 45° C., and 6-8 h at room temperature (RT). After the reaction was complete, the resin was filtered, washed with a 2:1 mixture of dichloromethane and methanol (1×8 ml), methanol (2×8 ml), and THF, and the acylation was repeated using the same loads of the reagents, but shorter reaction time: 4 hours at 45° C. and 2 hours at room temperature. At the end, the α-chloroacetamide loaded resin was filtered, washed with a 2:1 mixture of dichloromethane and methanol (1×8 ml), methanol (3×8 ml), and suck dried for 15 min under argon.

[0136] 4. Addition of the second amine. Synthesis of resin attached N-Geranyl-N′-(2-adamantyl)acetamide. The tube with the resin was charged with DMF (3 ml) and EtN(iPr)₂ (0.6 ml, 4.4 mmol), followed by the addition of a suspension of 2-adamantamine hydrochloride (2.0 g, 1.1 mmol) in DMF (4 ml), and was allowed to stir at 70-75° C. for 16 hours. After cooling down to the room temperature, the resin was filtered, washed with a 1:1 mixture of DCM and methanol (1×8 ml), methanol (2×8 ml), and suck dried for 15 minutes under argon.

[0137] 5. Reduction with Red-Al. Synthesis of resin attached N-Geranyl-N′-(2-adamantyl)ethane-1,2-diamine. The resultant resin was suspended in anhydrous THF (3 ml) in a tube, and stirred for 15 min. Commercially available Red-Al, 65+w % in toluene, was added (2.0 ml, 6.4 mmol), followed by addition of 2-3 ml of anhydrous THF (to fill up the volume of the tube). The mixture was allowed to react for 4 hours. After the reaction, the resin was filtered, washed with THF (1×8 ml), a 1:1 mixture of THF and methanol (1×8 ml) (addition of MeOH should proceed with caution), methanol (3×8 ml), and then dried.

[0138] 6. Cleavage from the resin and purification. Synthesis of N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine acetate. For this last step of the synthesis, the tube with the resin was charged with a 10:90 mixture of TFA and dichloromethane, and the formed bright red suspension was allowed to stir for 30 min. After addition of MeOH (0.5 ml), the colorless suspension was filtered, and the filtrate was collected into a proper tube. The procedure was repeated, and solvents were evaporated on a SPEEDVAC®. Half of the amount of crude N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine (in a form of trifluoroacetate salt) was purified by HPLC using following conditions: column C18, flow 4 ml/min, 30 min run, gradient starting with 5%AcOH/MeOH (100%) finishing up with acetonitrile (100%). Obtained: 27 mg of N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine diacetate, 24% yield, 98% purity by NMR.

EXAMPLE IV Representative Solution Phase Synthesis of the Active Compounds

[0139] Preparation of N-(Cyclooctyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine as hydrochloride (compound 59) is set forth in FIG. 13.

[0140] Bromocyclooctylacetylamide. To a mixture of cyclooctylamine (3.3 g, 0.026 mol) and pyridine (2.42 g, 0.031 mmol) in anhydrous THF (80 ml) at 0° C. was added dropwise, via syringe, bromoacetylbromide (5.78 g, 0.029 mol). The reaction temperature was maintained by an ice bath. The reaction mixture was allowed gradually to warm up to room temperature, and was stirred at room temperature for 1 hour. The precipitate was removed by filtration, washed with ethyl ether (1×30 ml), and the filtrate was concentrated to dryness on a rotory evaporator. Bromocyclooctylacetylamide was forwarded to the second step without additional purification.

[0141] N-(Cyclooctyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheyl-1-carbonylethane-1,2-diamine. To a solution of the bromocyclooctylacetylamide in DMF (60 ml) were added Hunig's base (4.64 g, 0.036 mol) and (1R,2R,3R,5S)-(−)-isopinocampheylamine (4.5 g, 0.029 mol), and the reaction mixture was stirred at 80° C. for 16 hours. After cooling off to the room temperature, the reaction mixture was diluted with 150 ml of ethyl ether, and washed with 1M NaOH solution (2×50 ml). The organic layer was washed with brine (1×50 ml), dried over MgSO₄, and concentrated to dryness on the rotory evaporator. The residue (11.04 g) as brown oil was purified on COMBIFLASK® (Isco, Lincoln, Nebr., USA), using Silicagel catridges commercially available from BIOTAGE® (Biotage, Inc. of Dyax Corp, Va, USA), and the following mobile phase gradient: 30 min run, starting with DCM, 100%, and finishing up with a mixture DCM:MeOH:NH₄OH (600:400:10). The final product (7.29 g) was obtained as a brown oil; 76% yield, purity 90%.

[0142] N-(Cyclooctyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine. To a solution of the amide, from previous step, in anhydrous THF (160 ml), was added dropwise via syringe commercially available (SIGMA-ALDRICH®) Red-Al, as 65 wt % solution in THF (28 ml, 0.09 mol). The reaction mixture was stirred at reflux for 20 hours. After cooling down to the room temperature, the reaction mixture was poured into 1.5M NaOH (200 ml), and extracted with ethyl ether (2×100 ml). The organic layer was washed with brine (1×100 ml), dried over MgSO₄, and evaporated to dryness on the rotory evaporator to yield 7.2 g of a crude product, as a brown oil. Chromatographic purification of the crude using the same equipment and conditions as for the previous step, gave 3.5 g of the diamine. The diamine was treated with 2.0M solution of HCl in ethyl ether (25 ml), and kept in a refrigerator overnight. A dark yellow solid (4.2 g) formed, and was filtered off, and recrystallized from MeOH and ethyl ether to yield 1.5 g of the diamine as an HCl salt (of purity greater than 98%, NMR and MS are available), 19% overall yield.

EXAMPLE V Mass Spectroscopy Analysis

[0143] Mass spectra data were obtained by Elecrospray Ionization technique on a PERKIN ELMER®/SCIEX®, API-300, TQMS with an autosampler, manufactured by SCIEX®, Toronto, Canada.

[0144] A. Library of Substituted Ethylenediamines

[0145] Mass spectroscopy served as a means for monitoring the reaction results of the library of ethylenediamines. Mass spectroscopy was done on two randomly selected rows (24 samples) per reaction plate, for roughly 28,000 compounds in pool of 10 or 30 compounds per well. Thus, if ten compounds per well were synthesized, the mass spectra for each well should contain ten signals, correlating with the proper molecular ions for each compound. The presence or absence of a particular signal indicated the feasibility of the particular synthesis. Based on the mass spectral data, and on a general analysis of the reactivity of the various amines, it is estimated that 67,000 compounds were formed out of 112,000 compounds.

[0146]FIG. 14 is a representative mass spec profile for one sample well. Mass spectra for a representative ethylene diamine compound is shown in FIG. 15. Tables 5 to 8, below, list illustrative examples of mass spec data for representative reaction wells, with each well containing ten substituted ethylene diamines. TABLE 5 ILLUSTRATIVE EXAMPLES OF MASS SPEC DATA FOR REPRESENTATIVE ETHYLENEDIAMINES (TEN COMPOUNDS PER WELL). R₂R₃NH in the 2^(nd) position R₁NH₂ in the 1^(st) position (pool of (from the master plate of [M + 1]⁺ of the product 10 resins) the amines) R₁NHCH₂CH₂NR₂R₃ Plate #4-034-2, well D10 1-(2-Aminoethyl)piperidine 2-Aminoheptane 270 absent Phenethylamine 263 4-(2-Aminoethyl)morpholifle 272 absent Tryptamine 302 Cyclohexylamine 241 Exo-2-Aminonorbomane 253 Benzylamine 249 2-Fluorophenethylamine 281 ? -Methylphenethylamine 277 4-Methoxyphenethylamine 293 Plate #4-56-1, well C4 4-Methylbenzylamine exo-2-Aminonorbornane 259 Cyclopentylamine 223 2-(Aminomethyl)piperidifle 246 low intensity Furfurylamine 235 3,4,5-Trimethoxybenzylamine 335 1-Methy1-3-phenylpropylamine 287 Cylcobutylamine 209 1,2,3,4-Tetrahydro-1-naphthylamine 258 2,3-Dimethy1cyclohexylamime 265 2-Amino-1-butanol 227 low intensity Plate #4-44-2, well G1 Veratrylamine 4-Fluorophenethylamine 333 2-(1-Cyclohexenyl)ethylamine 291 5-Aminoquinolone 310 absent 1-(1-Naphthyl)ethylamine 337 absent 1-Aminopiperidine 266 3-Fluorobenzylamine 291 2,4-Dimethoxybenzylamine 333 3-Amino-1,2,4-triazine 262 absent 2-Ethoxybenzylamine 317 4-(3-Aminopropyl)morpholine 310 absent

[0147] TABLE 6 Mass Spec Data for Synthesized Ethylenediamines

[M + 1]⁺ of the [M + 1]⁺ of the products, R₄ = Ph R₁NH₂ in the 1^(st) position products, R₄ = H Diamines, 1 Amino alcohols, 13 Tyramine 308 384 258 formed 2-Adamantamine 321 absent 398 absent 272 formed cis-Myrtanylamine 324 400 274 formed 3-Amino-1-propanol 246 322 196 absent L-Methioninol 305 absent 382 absent 256 absent Cyclooctylamine 298 374 248 formed (1S,2S)-2-Amino-1-phenyl- 337 absent 414 absent 288 absent 1,3-propandiol 1-Adamantanemethylamine 336 412 absent 286 formed 2,2-Diphenylethylamine 368 444 318 formed 5-Amino-1-pentanol 274 350 224 formed

[0148] TABLE 7 Mass Spec Data for Synthesized Ethylenediamines, R₄ = H and Me

[M + 1]⁺ of the [M + 1]⁺ of the products, R₄ = Me R₁NH₂ in the 1^(st) position products, R₄ = H Diamines, 1 Amino alcohols, 13 Tyramine 278 293 196 absent 2-Adamantamine 293 absent 307 absent 210 low intensity cis-Myrtanylamine 293 309 212 formed 3-Amino-1-propanol 217 231 134 absent L-Methioninol 277 absent 291 absent 194 formed Cyclooctylamine 269 269 absent 186 absent (1S,2S)-2-Amino-1-phenyl- 309 low intensity 323 absent 226 formed 1,3-propandiol 1-Adamantanemethylamine 307 321 224 formed 2,2-Diphenylethylamine 339 353 256 formed 5-Amino-1-pentanol 245 259 162 absent

[0149] TABLE 8 Mass Spec Data for Synthesized Ethylenediamines, R₄ = H and Me

[M + 1]⁺ of the [M + 1]⁺ of the products, R₄ = Me R₁NH₂ in the 1^(st) position products, R₄ = H Diamines, 1 Amino alcohols, 13 Tyramine 278 292 absent 196 absent 2-Adamantamine 292 absent 306 absent 210 formed cis-Myrtanylamine 294 308 absent 212 formed 3-Amino-1-propanol 216 230 absent 134 absent L-Methioninol 276 absent 290 absent 194 absent Cyclooctylamine 268 282 absent 186 absent (1S,2S)-2-Amino-1-phenyl- 308 322 absent 226 formed 1,3-propandiol 1-Adamantanemethylamine 306 absent 320 absent 224 formed 2,2-Diphenylethylamine 338 352 absent 256 formed 5-Amino-1-pentanol 244 258 absent 162 absent

EXAMPLE VI ¹H NMR Spectroscopy

[0150] Proton NMR data was recorded on a VARIAN® Nuclear Magnetic Resonance Spectrometer (Palto Alto, Calif.) at 500 MHz.

[0151] Representative substituted ethylene diamines were purified by HPLC, and analyzed by proton NMR. A representative proton NMR profiles is shown in FIG. 16. NMR and MS data for some representative hit compounds are shown below.

[0152] Compound 6.

[0153] N²-(1-Adamantylmethyl)-N¹-(3,3-diphenylpropyl)propane-1,2-diamine. 55 mg, 36% yield. ¹H NMR: δ 7.28-7.15 (m, 5H), 3.95 (t, J=7.9 Hz, 1H), 2.94 (br s 4H), 2.71 (dd, J=7.6, 9.8 Hz, 2H), 2.41 (s, 2H), 2.32 (dd, J=7.6, 7.9 Hz, 2H), 2.16 (s), 2.08-1.98 (m, 4H), 1.72 (m, 6H), 1.62 (m, 6H), 1.51 (d, J=2.4 Hz, 3H). Mass spectrum (ESI) m/z (MH)⁺ 417.

[0154] Compound 7.

[0155] N-(3,3-Diphenylpropyl)-N′-(1-adamanthylmethyl)ethane-1,2-diamine. 28 mg, 22% yield. 1H NMR (500 MHz) δ 7.30-7.12 (m, 10H); 3.95 (t, J=7.6 Hz, 1H); 2.91 (d, J=1.2 Hz, 4H); 2.70 (dd, J=7.6 and 1.2 Hz, 2H); 2.40 (d, J=1.3 Hz, 2H); 2.32 (q, J=8.0 Hz, 2H); 1.98 (br d, J=1.7 Hz, 4H); 1.72 (d, J=12.2 Hz, 4H); 1.62 (d, m? J=12.2 Hz, 4H); 1.51 (br s, 6H). Mass spectrum (ESI) m/z (MH)⁺ 403.6.

[0156] Compound 10.

[0157] N-(−)-cis-Myrtanyl-N′-(3,3-diphenylpropyl)ethane-1,2-diamine. 14 mg, 11% yield. 1H NMR (500 MHz) δ 7.30-7.10 (m, 10H); 3.95 (m, 1H); 2.92-2.83 (m, 4H); AB: 2.80 (d, J=7 Hz, 1H); 2.76 (d, J=8 Hz, 1H); 2.65 (dd, J=9.6 and 7.6 Hz, 2H); 2.42-2.20 (m, 4H), 2.29 (d, J=8 Hz, 2H), 1.90 (m, 8H); 1.42 (m, 1H); 1.19 (m, 2H); 1.17 (s, 3H); 0.95 (s, 3H); 1.00-0.8 (m, 2H). Mass spectrum (ESI) m/z (MH)⁺ 391.3.

[0158] Compound 14.

[0159] N-(3,3-Diphenylpropyl)-N′-exo-(2-norborny)ethane-1,2-diamine. 17 mg, 16% yield. 1H NMR (500 MHz) δ 7.30-7.15 (m, 1 OH); 3.95 (t,J=7.9 Hz, 1H); 2.86 (dd, J=11.5 and 1.5 Hz, 4H); 2.73 (dd, J=8.0 and 3.3 Hz, 1H); 2.64 (t, J=7.6 Hz, 2H); 2.29 (t, J=7.5 Hz, 2H), 2.31-2.26 (m, 2H) 2.30 1.96 (s, 3H); 1.63 (ddd, J=13.1, 7.9 and 2.5 Hz, 1H); 1.60-1.50 (m, 1H); 1.50-1.43 (m, 2H); 1.30 (dq, J=4.0 and 13.5 Hz, 1H), (1H, m), 1.20 (dd, J=10.4 and 1.1 Hz, 1H), 1.11 (dd, J=2.0, and 8.5 Hz, 1H), 1.08 (dd, J=2.5, and 8.5 Hz, 1H), 1.10 (dq, J=8.3 and 2.1, 2H). Mass spectrum (ESI) m/z (MH)⁺ 349.1.

[0160] Compound 21.

[0161] N-(3,3-Diphenylpropyl)-N′-(1S)-(1-ethylcyclohexane)ethane-1,2-diamine. 5 mg, 4% yield. Mass spectrum (ESI) m/z (MH)⁺ 365.5.

[0162] Compound 32.

[0163] N-(2,2-Diphenylethyl)-N′-®-(+)-bornylethane-1,2-diamine. 58 mg, 48% yield. 1H NMR (500 MHz): δ 7.30-7.10 (m, 10H); 4.18 (t, J=6.8 Hz, 1H); 3.34 (d, J=7.6 Hz, 2H); 3.02 (m, 4H); 2.95-2.90 (m, 1H); 2.15-2.08 (m, 1H); 1.94 (m, 1H); 1.72-1.65 (m, 2H); 1.48-1.30 (m, 2H); 1.27-1.10 (m, 2H); 1.06 (dd, J=13.6 and 4.1 Hz, 1H); 0.82 (s, 3H); 0.81 (s, 3H); 0.78 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 377.2

[0164] Compound 34.

[0165] N-(2,2-Diphenylethyl)-N′-(1-adamanthylmethyl)ethane-1,2-diamine. 6.8 mg, 6% yield. 1H NMR (500 MHz) δ 7.30-7.15 □m, 10H); 4.15 (t, J=7.6 Hz, 1H); 3.24 (dd, J=7.9 and 1.2 Hz, 2H); 2.79 (t, J=6.5 Hz, 2H); 2.74 (t, J=6.0 Hz,m, 2H); 1.95 (m, 8H); 1.69 (d, J=12.5 Hz, 4H); 1.59 (d, J=11.9 Hz, 4H); 1.40 and 1.39 (br s, 3H); Mass spectrum (ESI) m/z (MH)⁺ 389.0.

[0166] Compound 37.

[0167] N-(2,2-Diphenylethyl)-N′-(−)-cis-myrtanylethane-1,2-diamine. 54 mg, 38% yield. ¹H NMR: δ 7.31-7.18 (m, 10H), 4.13 (t, J=7.6 Hz, 1H), 3.26 (d, J=7.6 Hz, 2H), 2.86 (dd, J=4.3, 8.0 Hz, 4H), 2.76 (dd, J=7.6, 12.2 Hz, 2H), 2.37 (ddd, J=1.8, 9.0, 12.5 Hz, 1H), 2.12 (dq, J=1.8, 7.6 Hz, 1H), 1.98 (br s, 2H), 1.98-1.84 (m, 4H), 1.39 (ddd, J=2.4, 4.0, 6.1 Hz, 1H), 1.18 (s, 3H), 0.95 (s, 3H), 0.91 (d, J=10.0 Hz, 1H) Mass spectrum (ESI) m/z (MH)⁺ 377.2.

[0168] Compound 38.

[0169] N-(−)-cis-Myrtanyl-N′-(2,2-diphenylethyl)propane-1,2-diamine. 39 mg, 30% yield. 1H NMR (500 MHz) δ 7.30-7.15 (m, 10H); 4.13 (t, J=8.0 Hz, 1H); AB: 3.28 (d, J=7.5 Hz, 1H); 3.24 (d, J=7.5 Hz, 1H), 3.26 (d, J=6.1 Hz, 2H); 2.96 (m, 1H); 2.88-2.75 (m, 2H); 2.71 (ddd, J=4.5, 9.0, 13.0 Hz, 1H), 2.58 (ddd, J=7.0, 10.0, 14.0 Hz, 1H); 2.35 (m, 1H); 2.21 (m, 1H); 2.00-1.80 (m, 6H); 1.40-1.20 (m, 1H); 1.17 (s, 3H); 0.93 (s, 3H); 0.89 (dd, J=9.7 and 4.2 Hz, 1H). Mass spectrum (ESI) m/z (MH)⁺ 391.0.

[0170] Compound 40.

[0171] N-(2,2-Diphenylethyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine. 33 mg, 23% yield. ¹H NMR: δ 7.31-7.18 (m, 10H), 4.13 (t, J=7.5 Hz, 1H), 3.27 (d, J=8.0 Hz, 2H), 3.14 (dt, J=6.0, 10 Hz, 1H), (4H), 2.36 (qd, J=2.0, 6.0 Hz, 1H), 2.34 (dt, J=2.0, 10 Hz, 1H), 2.07-1.96 (m, 3H), 1.82 (dt, J=2.0, 6.0 Hz, 1H), 1.71 (ddd, J=2.5, 5.5, 13.5 Hz, 1H), 1.22 (s, 3H), 1.09 (d, J=7.0 Hz, 3H), 0.96 (d, J=10.5 Hz, 1H), 0.91 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 377.3.

[0172] Compound 47.

[0173] N-(−)-cis-Myrtanyl-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine. 42 mg, 33% yield. ¹H NMR: δ 3.35-3.20 (m, 6H), 2.93 (dd, J=4.6, 2.0 Hz, 2H), 2.45-2.33 (m, 4H), 2.17 (s, 3H), 2.06 (quint, J=7.0 Hz, 1H), 2.0-1.9 (m, 6H), 1.90 (dd, J=2.1, 5.2 Hz, 1H), 1.87 (dt, J=1.8, 4.6 Hz, 1H), 1.51 (ddd, J=4.6, 10.0, 13.0 Hz, 1H), 1.23 (s, 3H), 1.19 (s, 3H), 1.12 (d, J=8 Hz, 3H), 1.03 (d, J=10.3 Hz, 1H), 0.98 (s, 3H), 0.94 (d, J=9.8 Hz, 1H), 0.94 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 333.6.

[0174] Compound 52.

[0175] N-(3,3-Diphenylpropyl)-N′-cyclooctylethane-1,2-diamine. 20 mg, 18% yield. 1H NMR (500 MHz): δ 7.30-7.10 (m, 10H); 3.96 (t, J=7.9 Hz, 1H); 3.00 (m, 1H); 2.90 (dd, J₁=J₂=5.5 Hz, 2H); 2.84 (dd, J₁=J₂=5.0 Hz, 2H); 2.61 (t, J=7.3 Hz, 2H), 2.27 (q, J=7.6 Hz, 2H); 1.83 (m, 2H); 1.74 (m, 2H); 1.65-1.40 (m, 10H).

[0176] Compound 55.

[0177] N-(1-Adamantylmethyl)-N′-cyclooctylethane-1,2-diamine. 6.7 mg, 6% yield. 1H NMR (500 MHz): δ 3.08-3.02 (m, 1H), 3.02-2.98 (m, 2H); 2.97-2.92 (m, 2H); 2.36 (s, 2H); 1.98 (m, 2H); 1.93-1.86 (m, 2H); 1.80-1.50 (m, 19H).

[0178] Compound 57.

[0179] N-(−)-cis-Myrtanyl-N′-(cyclooctyl)ethane-1,2-diamine. 18 mg, 18% yield. 1H NMR (500 MHz) δ 3.05-2.95 (m, 4H); AB: 2.76 (d, J=7.5 Hz, 1H), 2.23 (d, J=8.0 Hz, 1H); 2.76 (dd, J=11.6 and 7.3 Hz, 1H); 2.73 (dd, J=11.9 and 8.2 Hz, 1H); 2.40-2.34 (m, 1H); 2.28 (quintet, J=8.0 Hz, 1H); 1.97 (s, 3H); 2.00-1.84 (m, 6H); 1.80-1.70 (m, 2H); 1.68-1.38 (m, 11H); 1.18 (s, 3H); 0.97 (s, 3H); 0.92 (d, J=9.8 Hz, 1H). Mass spectrum (ESI) m/z (MH)⁺ 307.5.

[0180] Compound 58.

[0181] N-(2-Adamantyl)-N′-cyclooctylethane-1,2-diamine. 25 mg, 23% yield. ¹H NMR: δ 3.06 (m, 1H), 3.00 (t, J=6.1 Hz, 2H), 2.93 (t, J=5, 5 Hz, 2H), 2.83 (br s, 1H), 1.96 (s, 3H), 1.92-1.80 (m, 10H), 1.80-1.50 (m, 20H). Mass spectrum (ESI) m/z (MH)⁺ 305.1.

[0182] Compound 59.

[0183] N-(Cyclooctyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine. 15 mg, 14% yield. 1H NMR (400 MHz): δ 3.47 (dt, J=6.0, 10.0 Hz, 1H), 3.40-3.28 (m, 7H), 2.44 (tq, J=2.0, 10.0 Hz, 1H), 2.36 (dtd, J=2.0, 6.0, 10.0 Hz, 1H), 2.09 (dq, J=2.0, 7.2 Hz, 1H), 2.00-1.90 (m, 3H), 1.88-1.78 (m, 2H), 1.78-1.63 (m, 4H), 1.65-1.30 (m, 8H), 1.18 (d, J=6.0 Hz, 3H), 1.16 (s, 3H), 1.17 (d, J=7.2 Hz, 1H), 0.90 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 307.4.

[0184] Compound 62.

[0185] N-(−)-cis-Myrtanyl-N′-(1S)-(1-ethylcyclohexane)ethane-1,2-diamine. 48 mg, 46% yield. 1H NMR (500 MHz): δ 3.06-3.00 (m, 1H); 2.98-2.95 (m, 2H); 2.92-2.84 (m, 1H); 2.79 (dd, J=11.9 and 7.0 Hz, 1H); 2.75 (dd, J=11.9 and 7.9 Hz, 1H); 2.73 (m, 1H); 2.39 (m, 1H); 2.28 (quintet, J=8.5 Hz, 1H); 2.00-1.86 (m, 6H); 1.82-1.76 (m, 2H); 1.68 (m, 2H); 1.54-1.42 (m, 2H); 1.32-1.10 (m, 6H); 1.19 (s, 3H); 1.13 (d, J=6.7 Hz, 3H); 1.07 (dd, J=12 and 3 Hz, 2H); 1.02 (dd, J=12 and 3 Hz, 2H); 0.98 (s, 3H); 0.93 (d, J=9.7 Hz, 1H). Mass spectrum (ESI) m/z (MH)⁺ 306.9.

[0186] Compound 65.

[0187] N-trans-(2-phenylcyclopropyl)-N′-(1-adamanthyl)ethane-1,2-diamine. 18 mg, 16% yield. Mass spectrum (ESI) m/z (MH)⁺ 311.3.

[0188] Compound 66.

[0189] N-(3,3-Diphenylpropyl)-N′-(1R,2R,3R,5S)-(−)-isopinocampheylethane-1,2-diamine. 2 mg, 2% yield. 1H NMR (500 MHz) δ 7.26 (m, 10H); 3.96 (t, J=7.6 Hz, 1H); 3.09 (m, 1H); 2.92 (m, 1H); 2.84 (m, 2H); 2.62 (m, 2H); 2.35 (m, 4H); 1.97 (s, 3H); 1.82 (m, 1H); 1.68 (m, 1H); 1.21 (s, 3H); 1.12 (d, J=7.3 Hz; 3H); 1.01 (m, 1H); 0.92 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 391.4.

[0190] Compound 73.

[0191] N-(2-Adamantyl)-N′-[2-(2-methoxyphenyl)ethyl]ethane-1,2-diamine. 21 mg, 19% yield. ¹H NMR: δ 7.22 (dd, J=8.2, 7.3 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H), 6.89 (d, J=7.1, Hz, 1H), 6.87 (d, J=8.2, Hz, 1H), 3.81 (s, 3H), 3.06 (t, J=7.1 Hz, 2H), 3.06 (m, 2H), 3.01 (m, 2H), 2.93 (t, J=7.1, 2H), 1.95 (br s, 2H), 1.90-1.80 (m, 7H), 1.78-1.66 (m, 6H), 1.59 (d, J=2.5 Hz, 2H). Mass spectrum (ESI) m/z (MH)⁺ 329.4.

[0192] Compound 78.

[0193] N-2-Adamantyl-N′-2,3-dihydro-1H-inden-2-yl-ethane-1,2-diamine. 4.3 mg, 3% yield. ¹H NMR: δ 7.20 (dd, J=4.9, 8.5 Hz, 2H), 7.14 (dd, J=5.5, 2.1 Hz, 2H), 3.71 (quint, J=6.1 Hz, 2H), 3.19 (dd, J=5.8, 15.9 Hz, 2H), 3.13 (br.s, 1H), 3.05 (m, 4H), 2.86 (dd, J=4.8, 15.8 Hz, 2H), 2.08 (m, 2H), 2.00 (m, 6H), 1.96-1.88 (m, 4H), 1.88-1.80 (m, 3H), 1.74 (m, 4H), 1.68-1.60 (m, 2H). Mass spectrum (ESI) m/z (MH)⁺ 303.4.

[0194] Compound 109.

[0195] N-Geranyl-N′-(2-adamanthyl)ethane-1,2-diamine. 27 mg, 24% yield. 1H NMR (400 MHz): δ 5.40 (t, J=7.2 Hz, 1H), 4.78 (br s, 2H), 3.64 (d, J=7.6 Hz, 2H), 3.34 (m, 2H), 2.07 (m, 2H), 2.08-1.95 (m, 4H), 1.95-1.85 (m, 4H), 1.82 (m, 2H), 1.88-1.70 (m, 4H), 1.70-1.62 (m, 3H), 1.67 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 307.4.

[0196] Compound 111.

[0197] N-Geranyl-N′-(2-ethylpiperidine)ethane-1,2-diamine. 44 mg, 42% yield. 1H NMR (500 MHz): δ 5.22 (t, J=6.1 Hz, 1H); 5.04 (m, 1H), 3.52 (d, J=7.3 Hz, 2H); 3.05-2.85 (m, 4H); 2.66 (m, 1H); 2.44 (m, 2H); 2.08 (m, 4H); 1.80-1.50 (m, 2H); 1.70(s, 3H); 1.65 (s, 3H); 1.58 (s, 3H); 1.50-1.35 (m, 2H), 0.89 (t, J=7.3, 3H). Mass spectrum (ESI) m/z (MH)⁺ 293.4.

[0198] Compound 116.

[0199] N-Geranyl-N′-allyl-N′-(cyclopentyl)ethane-1,2-diamine. 45 mg, 42% yield. ¹H NMR: δ 5.86 (ddd, J 10.0, 16.1, 6.7 Hz, 1H), 5.28 (d, J=15.9 Hz, 1H), 5.25 (d, J=8.7 Hz, 1H), 5.23 (t, J=7.3 Hz, 1H), 5.30 (m, 1H), 3.59 (d, J=7.3 Hz, 2H), 3.28 (br d, J=6.4 Hz, 2H), 3.16 (quintet, J=8.2 Hz, 1H), 3.02 (m, 2H), 2.95-2.86 (m, 2H), 1.88-1.80 (m, 4H), 1.70 (s, 3H), 1.74-1.66 (m, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.56-1.50 (2H), 1.50-1.40 (m, 2H). Mass spectrum (ESI) m/z (MH)⁺ 305.3.

[0200] Compound 117.

[0201] N-Geranyl-N′-diphenylmethylethane-1,2-diamine. 24 mg, 20% yield. 1H NMR (500 MHz): δ 7.40 (d, J=7.2 Hz, 4H); 7.29 (t, J=7.3 Hz, 4H); 7.21 (t, J=7.0 Hz, 2H); 5.15 (t, J=7.5, 1H); 5.01 (m, 1H); 4.89 (br s, 1H); 3.42 (d, J=7.0 Hz, 2H); 3.00-2.78 2.93 (m, 4H); 2.20-2.00 2.17 (m, 4H); 1.63 (s, 3H); 1.59 (s, 3H); 1.56 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 363.3.

[0202] Compound 125.

[0203] N,N′-bis-(−)-cis-Myrtanylpropane-1,2-diamine. 82 mg, 70% yield. 1H NMR (500 MHz): δ 3.62 (m, 1H); 3.18 (dd, J=13.7 and 3.7 Hz, 1H); 3.05 (dt, J=11.5 and 7.5 Hz, 1H); 3.06-2.92 (m, 2H); 2.86 (dt, J=12.2 and 7.3 Hz, 1H); 2.40 (m, 4H); 2.06-1.84 (m, 10H); 1.56-1.46 (m, 2H); 1.37 and 1.36 (two d,J=6.7 and J=7.0 Hz, 3H); 1.20 (s, 3H); 1.19 (m, 3H), 0.99 and 0.98 (two s, 3H) Hz, H); 0.97 (s, 3H); 0.94 (two d, J=10.1 Hz, 2H). Mass spectrum (ESI) m/z (MH)⁺ 346.9.

[0204] Compound 151.

[0205] N-[2-(2-Methoxy)phenylethyl]-N′-(1R,2R,3R,5S)-(−)-isopinocampheyl-ethane-1,2-diamine. 67 mg, 60% yield. 1H NMR (500 MHz): δ 7.23 (t, J=5.8 Hz, 1H); 7.13 (dd, J=5.8 and 1.8 Hz, 1H); 6.88 (m, 2H); 3.81 (s, 3H); 3.13 (m, 1H); 3.1-3.0 (m, 3H); 3.01 (t, J=7.0 Hz, 2H); 2.89 (t, J=7.0 Hz, 2H); 2.42-2.35 (m, 2H); 2.00 (m, 3H); 1.82 (dt, J=6.0 and 2.0 Hz, 1H); 1.72 (ddd, J=2.5, 5.5, 13.5 Hz, 1H); 1.22 (s, 3H) 1.13 (d, J=7.3 Hz, 3H). 0.99 (d, J=10.1 Hz, 1H); 0.93 (s, 3H). Mass spectrum (ESI) m/z (MH)⁺ 331.5.

[0206] N-2-(2-Methoxyphenyl)ethyl-N′-allyl-N′-cyclopentyl-ethane-1,2-diamine. 8 mg, 7% yield. ¹H NMR: δ 7.26 (dd, J=7.3, 8.5, 1H), 7.18 (d, J=7.2 Hz, 1H), 6.91 (m, 2H), 5.61 ddd, (J=6.7, 17.0, 9.4 Hz, 1H), 5.13 (d, J=15.3 Hz, 1H), 5.10 (d,J=9.2 Hz, 1H), 3.83 (s, 3H), 3.13 (dd,J=7.0, 6.7 Hz, 2H), 3.10 (d,J=6.7 Hz, 1H), 3.00 (d, J=7.3 Hz, 1H), 3.05-2.90 (m, 2H), 2.97 (dd, J=8.2, 6.1 Hz, 2H), 2.75 (t, J=6.1 Hz, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.22 (m, 2H). Mass spectrum (ESI) m/z (MH)⁺ 311.4.

[0207] N²-(3-Phenylpropyl)-N¹-[2-(4-fluorophenyl)ethyl]-1-phenylethane-1,2-diamine. 23 mg, 19% yield. ¹H NMR: δ 7.35 (d, J=7.6 Hz, 2H), 7.34 (quart, J=7. Hz, 1H), 7.26 (d, J=6.4 Hz, 3H), 7.23 (d, J=7.6 Hz, 2H), 7.17 (dd, J=7.3, 6.4 Hz, 1H), 7.12 (d, J=7.0 Hz, 2H), 3.21 (m, 1H), 3.03 (ddd, J=4.2, 8.0, 12.8 Hz, 4H), 2.86 (t, J=8.0 Hz, 2H), 2.85-2.79 (m, J=12. Hz, 2H), 2.74-2.64 (m, 4H), 2.61 (t, J=7.7 Hz, 2H), 1.96 (quint, J=7.6 Hz, 2H). Mass spectrum (ESI) m/z (MH)⁺ 377.3.

EXAMPLE VII M. Tuberculosis Rv0341p Lucs Drug Response

[0208] Substituted ethylene diamines, as described herein, were tested on Mycobacterium tuberculosis using high-throughout screening assay with recombinant mycobacterial containing promoter fusion of luciferase to Rv0341 EMB-inducible promoter. This assay quickly and reliably identifies antimycobacterial activity in compound mixtures and/or in individual compounds. In this assay, bioluminescence increases when the mycobacteria is tested against an active compound, or an active compound mixture. During this assay, a theoretical yield of 100% was assumed for every unpurified substituted ethylene diamine, and the activity of each sample was compared to commercially available ethambutol (99.0% purity). Results were reported in LCPS, and % Max. LCPS based on the activity of EMB at 3.1 μM.

[0209] The substituted ethylene diamines were analyzed according to the following procedure. The diamines were dried in a speed vacuum to an approximate concentration of 6.3 mmoles per well. Each diamine, or diamine mixture, was then resuspended or dissolved in 200 μl of methanol for a concentration of 31.5 mM diamine(s). The diamine(s) solution was diluted to a concentration of 200 μM in 7H9 broth medium (a 1:15.75 dilution of the 31.5 mM stock, followed by a 1:10 dilution; each dilution in 7H9 broth medium). Next, 50 μl of the diluted diamine(s) solution was added to the first well of a row of twelve in an opaque, 96-well plate. The 7H9 broth medium, 25 μl, was added to each of the remaining wells (#2-12) in the row. The diamine(s) solution in “well one” was serially diluted by transferring 25 μl from “well one” to “well two”, and repeating a 25 μl transfer from “well two” to “well three”, and so on, on through “well eleven”. In “well eleven”, the extra 25 μl of solution was discarded. “Well twelve” was used as a growth control to assess background activity of the reporter strain. The plate was then covered and incubated at 37° C. for 24 hours. Immediately prior to analysis, the following substrates were prepared: a buffer solution containing 50 mM HEPES at pH 7.0 and 0.4% Triton X-100. Then, 0.25 ml of 1M DTT, and 14 μl of 10 mg/ml luciferin in DMSO were added to 5 ml of the buffer solution. This final solution (50 μl) was added to each of the twelve wells, immediately after the incubation period had run. The luminescence from each well was measured 20 minutes after the luciferin substrate was added, using a TOPCOUNT® (Downers, Grove, Ill.) NXT luminometer (55/well).

[0210] FIGS. 6-8 show typical assay data for the luciferase reporter strain containing an Rv0341 EMB-inducible promoter with serial dilution of 12 wells (1 row) of a 96-well library plate. FIG. 10 shows the number of substituted ethylene diamines with at least 10% luciferase activity, based on the activity of ethambutol at 3.1 μM.

[0211]FIG. 6 represents typical assay data in the luciferase reporter strain containing an Rv0341 EMB-inducible promoter. The data represents values obtained from the HTS Luc assay for compound mixtures of one row (row D) in the 96-well library. Row D was subject to several serial dilutions. The effectiveness of the compound mixture in the assay was measured by the intensity of luminescence, and compared to ethambutol (100% intensity, 99% purity) at 3.1 μM. Each curve in FIG. 6 represents one well, or ten compounds. Results are reported in percent maximum Luminescence Count per Second (% Max. LCPS). During the screening, a theoretical 100% chemical yield was assumed for every unpurified compound. Concentrations are given for a single compound. Based on this initial screening, 300+compound mixtures showed anti-TB activity.

EXAMPLE VIII Representative MIC Experiment

[0212] The Minimum Inhibition Concentration (MIC) is the concentration of the growth inhibitor, here a substituted ethylene diamine, at which there is no multiplication of seeded cells. A microdilution method was used to determine the MIC of the substituted ethylene diamines, capable of inhibiting the growth of Mycobacterium tuberculosis in vitro. In a representative MIC experiment, bacteria, the H37Rv strain of Mycobacterium tuberculosis (M. tb), was cultivated in 7H9 medium to a density of 0.2 OD (optical density) at 600 nm. The bacterial culture was then diluted 1:100 in 7H9 broth medium. Stock solutions of isoniazid and ethambutol were each prepared at 32 μg/ml in 7H9 medium. A 3.2 mg/ml solution of isonizid and ethambutol were each prepared in water. The solutions were then filtered, and diluted 1:100 in 7H9 medium. Each drug, purchased from Sigma, was “laboratory use only” grade. A 10 mM solution of each substituted ethylene diamine was prepared in methanol. Next, 100 μl of the 7H9 medium was added to each well in a 96-well plate (rows (A through H)×columns (1 through 12)). To the first wells in rows C through H was added an additional 80 μl of the 7H9 medium. The isoniazid solution, 100 μl, was added to well A1, and the ethambutol solution, 100 μl, was added to well B1. Six substituted ethylene diamines, 20 μl each, were added to wells C1 through H1 (column 1), respectively. A serial dilution of each substituted ethylene diamine and the isoniazid and ethambutol controls, was performed across each row. For example, a serial dilution across row C1-C12 was done by mixing and transferring 100 μl of the previous well to the next consecutive well. In each well in “column 12,” 100 μl of the final dilution was discarded. Next, 100 μl of the diluted H37Rv strain of M. tb was added to each well. The 96-well plate was then covered and incubated at 37° C. for 10 days. The plate was read for bacterial growth, or non-growth, using an inverted plate reader. The MIC was determined to be the lowest concentration of substituted ethylene diamine that inhibited visible growth of the M. tb.

[0213] A representative plate layout, listing concentration in each well, is shown in Table 9. Table 10 lists MIC and LD50 data for selected compounds. The LD50 is the concentration of the substituted ethylene diamine at which 50% of the cells (H37Rv strain of M. tb) are killed. Table 11 lists MIC data for purified substituted ethylene diamines in comparison to ethambutol (EMB). FIG. 9 shows the number of substituted ethylene diamine compounds with MIC activity at various concentration levels. TABLE 9 Concentration in Each Well (PM) Based on Columns 1-12 DRUG Isoniazid 58.25 9.13 14.56 7.28 3.64 1.82 0.91 0.45 0.23 0.11 0.06 0.03 Ethambutol 28.75 14.38 7.19 3.60 1.80 0.90 0.45 0.22 0.11 0.06 0.03 0.01 Subst. 500 250 125 62.5 1.25 15.63 7.81 3.91 1.96 0.98 0.49 0.24 Ethylene Diamine

[0214] TABLE 10 Selectivity Index for Selected Compounds Cmpd  MIC (uM) LD5O(uM) MW MIC (ug/ml) LD5O (ug/ml) SI 6 7.813 20 536 4.187768 10.72 2.559836 34 7.813 32 508 3.969004 16.256 4.095738 37 15.625 32 496 7.75 15.872 2.048 47 15.625 25 452 7.0625 11.3 1.6 57 15.625 18 426 6.65625 7.668 1.152 59 15.625 32 426 6.65625 13.632 2.048 65 15.625 60 430 6.71875 25.8 3.84 109 1.953 32 450 0.87885 14.41 6.38505 111 7.813 44 412 3.218956 18.128 5.63164 151 7.813 41 450 3.51585 18.45 5.247664

[0215] The above procedure was also used to examine batched compounds (10 compounds per well). Synthesized batches of substituted ethylene diamines were dried in speed vacuum and then resuspended in DMSO or sterile water to a concentration of 2.5 mg/ml. TABLE 11 MIC Data for Purified Samples Plate set-up INH  58.25 29.125 14.56 7.28 3.64 1.82 0.91 0.45 0.23 EMB  28.75 14.375 7.1875 3.594 1.797 0.898 0.449 0.2245 0.1125 CMPD 500 250 125 62.5 31.25 15.625 7.813 3.9063 1.953 Avg INH MIC (uM) Avg INH MIC (uM) 0.91 0.91 Avg EMB MIC (uM) Avg EMB MIC (uM) Avg EMB Avg EMB 7.1875 8.37 7.25 7.25 Cmpd MIC (uM) BACTEC EMB: 2.5 UG/ML 1 250 250 125 125 2 250 250 250 250 3 31.25 62.5 15.6 15.6 4 125 62.5 62.5 62.5 5 >500 500 500 500 6 7.813* 7.813 3.9 3.9 7 15.625* 7.813 3.9 3.9 8 125 125 31.25 31.25 10 7.813* 15.625 7.8 7.8 11 31.25 contaminated 3.9 3.9 13 31.25 31.25 15.6 15.6 15 14 15.625” 15.625 7.8. 7.8 15 >500 >500 250 500 17 62.5 62.5 15.6 15.6 21 15.625* 31.25 7.8 7.8 22 31.25 31.25 7.8 15.6 23 31.25 31.25 15.6 15.6 24 125 125 31.25 31.25 27 125 62.5 15.6 31.25 28 125 62.5 31.25 31.25 29 62.5 62.5 31.25 62.5 31 31.25 61.25 15.6 15.6 32 15.625* 15.625 7.8 7.8 33 62.5 62.5 31.25 31.25 34 7.813* 7.813 3.9 3.9 35 62.5 62.5 15.6 31.25 36 31.25 62.5 15.6 15.6 37 15.625* 15.625 3.9 7.8 1.25 38 7.813 7.813 3:9 7.8 40 15.625* 15.625 7.8 7.8 41 31.25 15.625 15.6 15.6 42 31.25 31.25 1.95 3.9 43 31.25 31.25 3.9 7.8 12.5 47 15.625* 15.625 1.95 7.8 5 51 31.25 250 31.25 31.25 52 15.625* 15.625 3:9 3.9 53 31.25 31.25 31.25 31.25 54 31.25 31.25 15.6 31.25 55 15.625* 15.625 15.6 15.6 25 56 500 >500 500 500 57 15.625* 7.813 7.8 7.8 58 15.625* 15.625 7.8 7.8 5 59 15.625* 31.25 15.6 15.6 12.5 61 62.5 62.5 31.25 31.25 62 15.625* 31.25 15.6 31.25 63 62.5 62.5 31.25 62.5 64 31.25 31.25 31.25 31.25 65 15.625* 31.25 31.25 31.25 66 15.625* 15.625 7.8 7.8 68 500 500 500 500 71 62.5 62.5 31.25 31.25 73 62.5 15.6 15.6 76 62.5 62.5 31.25 31.25 77 31.25 31.25 15.6 15.6 78 15.625* 31.25 15.6 15.6 79 31.25 31.25 15.6 15.6 103 31.25 31.25 62.5 62.5 107 500 500 250 250 109 1.953* 1.953 1.95 1.95 0.63 111 7.813* 7.813 7.8 7.8 5 116 15.625* 15.625 7.8 15.6 12.5 117 7.813* 15.625 7.8 7.8 118 31.25 62.5 31.25 nodata 119 125 62.5 cont no data contam 125 15.625* 15.625 cont no data 6.25 134 >500 >500 500 no data 151 15.625* 7813 cont no data 6.25 164 62.5 125 cont no data 165 62.5 62.5 15.6 15.6

EXAMPLE IX

[0216] Secondary Screening and Evaluation of Substituted Ethylene Diamines Against Drug Resistant Patient Isolates

[0217] Secondary screening was performed on some of the substituted ethylene diamine compounds to examine their activity against three clinically resistant MDR patient isolates. MDR Strain TN576 is classified as a W1 strain (STP^(R), INH^(R), RIF^(R), EMB^(R), ETH^(R), KAN^(R), CAP^(R)) strain TN587 is classified as a W strain (STP^(R), INH^(R), RIF^(R), EMB^(R), KAN^(R)), and the third strain TN3086 is classified as a W1 strain (STP^(R), INH^(R), RIF^(R), EMB^(R), KAN^(R)). Each MDR strain is highly resistant to ethambutol with MIC values exceeding 12.5-25 μM. The MICs for the following substituted ethylene diamines, MP 116, MP 117, RL 241, compounds #59 and #109, were determined for all three patient isolates.

[0218] The results from this study are shown in Tables 12-13. Table 14 characterizes each MDR strain according to its resistance. TABLE 12 Screening of Substituted Ethylene Diamines Against Drug Resistant Patient Isolates - (MIC values in ug/ml) WT 576 587 3806 EMB 3.12 (or 11.l uM) 12.5-25 12.5-25 12.5-25 MP 116 6.25 3.15 6.25 3.15 MP 117 6.25 3.15 3.15 3.15 RL 241  1.5 (or 3.34 uM) 1.5 1.5 1.5

[0219] TABLE 13 Screening of Substituted Ethylene Diamines Against Drug Resistant Patient Isolates - (MIC values in ug/ml) WT 576 587 3806 EMB 1.6-1.8 50 50 50 Cmpd #59 0.05 (or 0.13 uM) 0.1 0.05 0.05 Cmpd #109 0.10 (or 0.l8 uM) 0.2 0.2 0.1

Table 14

[0220] Drug Resistance of Each MDR Strain Strain STP STP2 INH1 INH2 Rif Emb Eth Kan Cip Cap Cyc 576 W1 R R R R R R R R S R S 587 W R R R R R R S R S S S 3806 W1 R R R R S R

EXAMPLE X In Vivo Animal Studies

[0221] Animal models were used in the final stages of the drug discovery cycle to assess the anti-microbial efficacy of some substituted ethylanediamine compounds in a representative system of human disease state. The in vivo testing approach involves the inoculation of four-six week old C57BL/6 mice via aerosol, containing approximately 200 colony forming units of M. tuberculosis H37R_(V).

[0222] A. CFU Lung Study

[0223] Mice aerosolized with M tuberculosis H37R_(V) were examined for 10 to 12 weeks following inoculation. Drugs (substituted ethylene diamines) were administered via the esophageal cannula (gavage) 7 days/week, starting at either 14 or 21 days post infection. Bacterial load in the lungs of five mice per group were determined at approximately one-week intervals by viable colony counts. The drugs tested were directly compared to the front line anti-tuberculosis drug isoniazid, and to the second line drug, ethambutol. Isoniazid and ethambutol were tested at 25 mg/kg and 100 mg/kg, respectively. The substituted ethylene diamines, compound 37, compound 59 and compound 109, were each tested at 1 mg/kg and 10 mg/kg. FIGS. 17 to 19 represent data from three, independent CFU Lung studies. In each study, the number of colony forming units (CFU) that were recoverable and cultivatable, were determined during various time intervals (days).

[0224] B. Lesion Study

[0225] The ability of compound 59 and compound 109 to prevent the development of gross pathology due to bacterial burden was determined in conjunction with the CFU/Lung Study. The gross pathology was determined by visible quantitation of lesions on the surface of the lungs. Quantitation by inspection is a good surrogate for CFU determination, and directly correlates to the bacterial burden, as determined by the actual colony forming units. The lesions are first visibly examined, and then the lungs are processed and plated for CFU quantification. The lesion study demonstrates the ability of the drug to prevent the development of the disease pathology. FIG. 20 represents data from a lesion study. The corresponding CFU results are shown in FIG. 19.

[0226] C. Toxicity Study

[0227] Toxicity was assessed using a dose escalation study. This study was performed with ten C57BL/6 mice per candidate. Every two days, the mice were administered an increased concentration of the drug, and monitored for detrimental effects. The administration scheme was 50, 100, 200, 400, 600, 800 and 1000 mg/kg. The maximum limit of 1000 kg/mg was based on the goal of dose escalation, and the solubility of the drugs in the delivery vehicle. Compound 37 was toxic in mice at 100 kg/mg. Compound 59 and compound 109 were tolerated in mice at 1000 mg/kg and 800 mg/kg, respectively.

[0228] It should be understood that the foregoing relates only to preferred embodiments of the present invention, and that numerous modifications, or alterations, may be made therein without departing from the spirit and scope of the invention. The entire text of each reference mentioned herein is hereby incorporated, in its entirety, by reference.

REFERENCES

[0229] 1. Dye, C.; Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C., “Consensus statement. Global Burden of Tuberculosis: Estimate Incidence, Prevalence, and Mortality By Country. WHO Global Survailance and Monitoring Project.” J. Am Med Association 1999, 282, 677-686.

[0230] 2. Bass, J. B.; Farer, L. S.; Hopewell, P. C.; O'Brein, R.; Jacobs, R. F.; Ruben, F.; Snider, D. E. Jr.; Thornton, G., “Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. The American Thoraic Society and the Canters for Disease Control and Prevention,” Am. J. Respir. Crit. Care Med. 1994, 149, 1359-1374.

[0231] 3. Farmer, P.; Bayona, J.; Becerra, M.; Furin, J.; Henry, C.; Hiatt, H.; Kim, J. Y.; Mitnick, C.; Nardell, E.; Shin, S., “The Dilemma of MDR-TB in the Global Era,” Int. J. Tuberc. Lung Dis. 1998, 2, 869-876.

[0232] 4. Pablos-Mendez, A.; Raviglione, M. C.; Laszlo, A.; Binkin, N.; Rieder, H. L.; Bustreo, F.; Cohn, D. L.; Lambregts van Weesenbeek, C. S.; Kim, S. J.; Chaulet, P.; Nunn, P., “Global Surveillance for Antituberculosis-drug Resistance,” 1994-1997. N. Engl. J. Med 1998, 338, 1641-1649. [Erratum, N. Engl. J. Med. 1998, 339, 139].

[0233] 5. Chan-Tack, K. M., “Antituberculosis-drug Resistance,” N. Engl. J. Med. 1998, 339, 1079.

[0234] 6. Cole, S. T.; Brosch, R.; Parkhill, J.; Gamier, T.; Churcher, C.; Harris, D.; Gordon, S. V.; Eiglmeier, K.; Gas, S.; Barry, C. E. 3^(RD); Tekaia; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Barrell, B. G., “Deciphering the Biology of Mycobacterium tuberculosis From The Complete Genome Sequence,” [published erratum appears in Nature Nov. 12, 1998; 396, 190]; Nature 1998, 393, 537-544.

[0235] 7. O'Brien, R. J., “Scientific Blueprint for Tuberculosis Drug Development,” The Global Alliance for TB Drug Development, Inc. 2001.

[0236] 8. Barry, C. E., III; Slayden, R. A.; Sampson, A. E.; Lee, R. E., “Use of Genomics and Combinatorial Chemistry in the Development of New Antimycobacterial Drugs,” Biochem. Pharmacol 2000, 59, 221.

[0237] 9. Cynamon, M. H.; Klemens, S. P.; Sharpe, C. A.; Chase, S., “Activities of Several Novel Oxazolidinones Against Mycobacterium Tuberculosis In A Murine Model,” Antimicrob Agents Chemother. 1999, 43, 1189-91.

[0238] 10. Shepard, R. G.; Baughn, C.; Cantrall, M. L.; Goodstein, B.; Thomas, J. P.; Wilkinson, R. G., “Structure-activity Studies Leading To Ethambutol, A New Type of Antituberculosis Compound,” Ann, N. Y. Acad. Sci 1966, 135, 686.

[0239] 11. Deng, L.; Mikusova, K.; Robuck, K. G.; Scherman, M.; Brennan, P. J., McNeil, M. R., “Recognition of Multiple Effects of Ethambutol on Metabolism of Mycobacterial Cell Envelope, “Antimicrob. Agents Chemother. 1995, 39, 694-701.

[0240] 12. Lee, R. E.; Mikusova, K.; Brennan, P. J.; and Besra, G. S.; “Synthesis of the Mycobacterial Arabinose Donor β-D-Arabinofuranosyl-1-monophosphoryl-decaprenol, Development of a Basic Arabinosyl-transferase Assay, and Identification of Ethambutol As An Arabinosyl Transferase Inhibitor,” J. Am. Chem. Soc. 1995, 117, 11829-11832.

[0241] 13. Belanger, A. E.; Bestra, G. S.; Ford, M. E.; Mikusova, K.; Belisle, J. T.; Brennan, P. J.; Inamine, J. M, “The EmbAB Genes of Mycobacterium avium Encode An Arabinosyl Transferase Involved in Cell Wall Arabinan Biosynthesis That is The Target for The Antimycobacterial Drug Ethambutol,” Proc. Natl. Acad. Sci USA 1996, 93, 11919.

[0242] 14. Telenti, A.; Phillip, W. J.; Sreevatsan, S.; Bernasconi, C.; Stockbauer, K. E.; Wieles, B.; Musser, J. M.; Jacobs, W.R. Jr., “The Emb Operon, A Gene Cluster of Mycobacterium Tuberculosis Involved in Resistance to Ethambutol,” Nat. Med. 1997, 3, 567.

[0243] 15. Cuervo, J. H.; Weitl, F.; Ostretch, J. M.; Hamashin, V. T; Hannah, A. L.; Houghten, R. A. in Peptides 1994: Proceedings of the European Peptide Symposium; Maia HSL Ed., Esom: Leiden, 1995, 465-466.

[0244] 16. Silen, J. L; Lu, A. T.; Solas, D. W.; Gore, M. A.; Maclean, D.; Shah, N. H.; Coffin, J. M.; Bhinderwala, N. S.; Wang, Y.; Tsutsui, K. T.; Look, G. C.; Campbell, D. A.; Hale, R. L.; Navre, M.; Deluca-Flaherty, C. R., “Screening For Novel Antimicrobials from Encoded Combinatorial Libraries by Using a Two-Dimensional Agar Format,” Antimicrob. Agents Chemother. 1998, 42, 1147.

[0245] 17. Gustafson, G. R.; Baldino, C. M.; O'Donnel, M.-M. E.; Sheldon, A.; Tarsa, R. J.; verni, C. J.; Coffen, D. L., “Incorporation of Carbohydrates and Peptides Into Large Triazine-based Screening Libraries Using Automated Parallel Synthesis,” Tetrahedron 1998, 54, 4067.

[0246] 18. H. Rink Tetrahedron Lett. 1987, 28, 3787.

[0247] 19. Garigipati, R. V., “Reagents for Combinatorial Organic Synthesis: Preparation and Uses of Rink-chloride,” Tetrahedron Lett. 1997, 38, 6807.

[0248] 20. Brown, D. S.; Revill, J. M.; Shute, R. E. Merrifield, “Alpha-Methoxyphenyl (MAMP) Resin; A New Versatile Solid Support for The Synthesis of Secondary Amines, “Tetrahedron Lett. 1998, 39, 8533.

[0249] 21. Zuckermann, R. N.; Kerr, S. B. H.; Moos, W. H., “Efficient Method for The Preparation of Peptoids [oligo(N-substituted glycines)] by Submonomer Solid-phase Synthesis,” J. Am. Chem. Soc. 1992, 114, 10646-10647.

[0250] 22. Gordon, D. W.; Steele, J., “Reductive Alkylation on a Solid Phase: Synthesis of a Piperazidione Combinatorial Library, Bioorg. Med. Chem. Lett. 1995, 5, 47.

[0251] 23. Liu, G.; Eliman J. A., “A General Solid-phase Synthesis Strategy for The Preparation of 2-Pyrrolidinemethanol Ligands,” J. Org. Chem. 1995, 60, 7712.

[0252] 24. March, J., “Advanced Organic Chemistry,” 3^(rd) Ed., Wiley, New York, p. 916.

[0253] 25. Luknitskii, Vovsi., Russ. Chem. Rev., 1969, 38, 487-494.

[0254] 26. Lee, M. H.; Pascopella, L.; Jacobs, W. R.; Hatfull, G. F., “Site Specific Integration of Mycobacteriophage L5: Integration-Proficient Vectors for Mycobacterium smegmatis, Mycobacterium tuberculosis, and bacilli Calmette-Guerin,” Proc. Matl Acad. Sci USA 1991, 88, 3111.

[0255] 27. Shawar, R. M.; Humble, D. J.; Van Dalfsen, J. M.; Stover, C. K.; Hickey, M. J.; Steele, S.; Mitscher, L. A.; Baker, W., “Rapid Screening of Natural Products for Antimycobacterial Activity By Using Luciferase-Expressing Strains of Mycobacterium bovis BCG and Mycobacterium intracellulare,” Antimicrob. Agents Chemother. 1997, 41, 570-574.

[0256] 28. Arain, T. M.; Resconi, A. E.; Hickey, M. J.; Stover, C. K., “Bioluminesence Screening In Vitro (Bio-Siv) Assays for High-Volume Antimycobacterial Drug Discovery,” Antimicrob. Agents Chemother. 1996, 40, 1536-1541. 

We claim:
 1. A composition comprising a substituted ethylene diamine compound of the formula

wherein R₄ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl; and wherein R₁, R₂ and R₃ are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or wherein R₁ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR₂R₂ is derived from a cyclic secondary amine.
 2. The composition of claim 1, wherein NHR₁ or NR₂R₃ of the substituted ethylene diamine has the chemical structure


3. The composition of claim 2, wherein the substituted ethylene diamine compound is


4. The composition of claim 2, wherein the substituted ethylene diamine compound is


5. The composition of claim 2, wherein the substituted ethylene diamine compound is


6. The composition of claim 2, wherein the substituted ethylene diamine compound is


7. The composition of claim 2, wherein the substituted ethylene diamine compound is


8. The composition of claim 2, wherein the substituted ethylene diamine compound is


9. The composition of claim 2, wherein the substituted ethylene diamine compound is


10. The composition of claim 2, wherein the substituted ethylene diamine compound is


11. The composition of claim 2, wherein the substituted ethylene diamine compound is


12. The composition of claim 2, wherein the substituted ethylene diamine compound is


13. The composition of claim 2, wherein the substituted ethylene diamine compound is


14. The composition of claim 2, wherein the substituted ethylene diamine compound is


15. The composition of claim 2, wherein the substituted ethylene diamine compound is


16. The composition of claim 1, wherein NHR₁ or NR₂R₃ of the substituted ethylene diamine has the chemical structure


17. The composition of claim 16, wherein the substituted ethylene diamine compound is


18. The composition of claim 16, wherein the substituted ethylene diamine compound is


19. The composition of claim 16, wherein the substituted ethylene diamine compound is


20. The composition of claim 16, wherein the substituted ethylene diamine compound is


21. The composition of claim 16 wherein the substituted ethylene diamine compound is


22. The composition of claim 16, wherein the substituted ethylene diamine compound is


23. The composition of claim 16, wherein the substituted ethylene diamine compound is


24. The composition of claim 16, wherein the substituted ethylene diamine compound is


25. The composition of claim 16, wherein the substituted ethylene diamine compound is


26. The composition of claim 16, wherein the substituted ethylene diamine compound is


27. The composition of claim 16, wherein the substituted ethylene diamine compound is


28. The composition of claim 16, wherein the substituted ethylene diamine compound is


29. The composition of claim 16, wherein the substituted ethylene diamine compound is


30. The composition of claim 16, wherein the substituted ethylene diamine compound is


31. The composition of claim 1, wherein NHR₁ or NR₂R₃ of the substituted ethylene diamine has the chemical structure


32. The composition of claim 31, wherein the substituted ethylene diamine compound is


33. The composition of claim 31, wherein the substituted ethylene diamine compound is


34. The composition of claim 31, wherein the substituted ethylene diamine compound is


35. The composition of claim 31, wherein the substituted ethylene diamine compound is


36. The composition of claim 31, wherein the substituted ethylene diamine compound is


37. The composition of claim 31, wherein the substituted ethylene diamine compound is


38. The composition of claim 31, wherein the substituted ethylene diamine compound is


39. The composition of claim 31, wherein the substituted ethylene diamine compound is


40. The composition of claim 31, wherein the substituted ethylene diamine compound is


41. The composition of claim 31, wherein the substituted ethylene diamine compound is


42. The composition of claim 31, wherein the substituted ethylene diamine compound is


43. The composition of claim 1, wherein NHR₁ or NR₂R₃ of the substituted ethylene diamine has the chemical structure


44. The composition of claim 43, wherein the substituted ethylene diamine compound is


45. The composition of claim 43, wherein the substituted ethylene diamine compound is


46. The composition of claim 43, wherein the substituted ethylene diamine compound is


47. The composition of claim 43, wherein the substituted ethylene diamine compound is


48. The composition of claim 1, wherein the substituted ethylene diamine compound is


49. The composition of claim 1, wherein the substituted ethylene diamine compound is


50. The composition of claim 1, wherein the substituted ethylene diamine compound is


51. The composition of claim 1, wherein the substituted ethylene diamine compound is


52. The composition of claim 1, wherein the substituted ethylene diamine compound is


53. The composition of claim 1, wherein the substituted ethylene diamine compound is


54. The composition of claim 1, wherein the substituted ethylene diamine compound is


55. The composition of claim 1, wherein the substituted ethylene diamine compound is


56. The composition of claim 1, wherein the substituted ethylene diamine compound is


57. The composition of claim 1, wherein the substituted ethylene diamine compound is


58. The composition of claim 1, wherein the substituted ethylene diamine compound is


59. The composition of claim 1, wherein the substituted ethylene diamine compound is


60. The composition of claim 1, wherein the substituted ethylene diamine compound is


61. The composition of claim 1, wherein the substituted ethylene diamine compound is


62. The composition of claim 1, wherein the substituted ethylene diamine compound is


63. The composition of claim 1, wherein the substituted ethylene diamine compound is


64. The composition of claim 1, wherein the substituted ethylene diamine compound is


65. The composition of claim 1, wherein the substituted ethylene diamine compound is


66. The composition of claim 1, wherein the substituted ethylene diamine compound is


67. The composition of claim 1, wherein the substituted ethylene diamine compound is


68. The composition of claim 1, wherein the substituted ethylene diamine compound is


69. The composition of claim 1, wherein the substituted ethylene diamine compound is


70. The composition of claim 1, wherein the substituted ethylene diamine compound is


71. The composition of claim 1, wherein the substituted ethylene diamine compound is


72. The composition of claim 1, wherein the substituted ethylene diamine compound is


73. The composition of claim 1, wherein the substituted ethylene diamine compound is


74. The composition of claim 1, wherein the substituted ethylene diamine compound is


75. A method of treating disease caused by a microorganism comprising administering an effective amount of a substituted ethylene diamine compound of the formula:

wherein R₄ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl; and wherein R₁, R₂ and R₃ are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or wherein R₁ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR₂R₂ is derived from a cyclic secondary amine.
 76. A method of preparing a substituted ethylene diamine compound of the formula

wherein R₄ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkynyl, cycloalkyl, cycloalkenyl; and wherein R₁, R₂ and R₃ are independently selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino; or wherein R₁ is selected from H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, and NR₂R₂ is derived from a cyclic secondary amine; comprising activating a solid-support resin containing hydroxyl groups with a halo-donating reagent in the presence of base to produce a solid-support resin containing halo groups; displacing the halo groups with an initial primary amine to produce a solid-support resin containing amine groups; acylating the amine groups with a halo-acylhalide in the presence of a basic compound, or with a halo-acylacid in the presence of base, to produce a solid-support resin containing α-haloacetyl amide groups; displacing α-halo groups of the α-haloacetyl amides with a secondary or subsequent primary amine to produce a solid-support resin containing α-amine imide groups; reducing the carbonyl moiety on the α-amine imide groups with a reducing agent to produce a solid-support resin containing two amine groups separated by two carbon atoms; cleaving the amine groups separated by two carbon atoms from the solid support resin in the presence of acid to produce the substituted ethylene diamine compound.
 77. The method of claim 76, wherein the initial primary amine is R₁NH₂.
 78. The method of claim 76, wherein the secondary or subsequent primary amine is R₂R₃HN. 